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Can persistent organic pollutants and plastic-associated chemicals cause cardiovascular disease?
Abstract
Lind L, Lind PM (Uppsala University, Uppsala, Sweden). Can persistent organic pollutants and plastic-associated chemicals cause cardiovascular disease? (Review). J Intern Med 2012; 271: 537–553.
During the last decade, associations between persistent organic pollutants (POPs), such as polychlorinated biphenyls, dioxins and pesticides, and cardiovascular (CV) risk factors and overt CV disease (CVD) have been reported in humans. Recently, associations between plastic-associated chemicals (PACs), such as bisphenol A and phthalates, and CVD have also begun to emerge. Several approaches to evaluating such associations have been used: accidents with a high level of exposure, occupational exposure studies, geographical studies of subjects living near a contaminated area and traditional case–control or cohort studies with measurements of circulating levels of different environmental contaminants in the general population. Exposure to POPs has consistently been associated with diabetes using all the approaches described above, including prospective studies. The evidence regarding associations between exposure to POPs and other CV risk factors, such as hypertension, obesity and lipids, is less strong and is mainly based on cross-sectional data. Associations between overt CVD and POPs have been reported using all the above approaches, but prospective data from population-based studies are still lacking to provide firm evidence of an important and independent role of POP exposure in the pathogenesis of CVD. Nevertheless, taken together, current evidence suggests that further longitudinal and experimental studies should be conducted to investigate the effect of exposure to both POPs and PACs, such as bisphenol A and phthalates.
... Atherosclerotic cardiovascular disease (CVD) is the leading cause of global morbidity and mortality [1,2]. In addition to the well-known contributing factors including unhealthy diet and sedentary lifestyles [3,4], exposure to environmental chemicals such as endocrine disrupting chemicals (EDCs) has been implicated in the etiology of CVD [2,[5][6][7]. For example, the ubiquitous plastic-associated EDCs including base chemical bisphenol A (BPA) and numerous plasticizers have been associated with increased CVD risk in humans [2,[5][6][7][8][9][10][11][12][13]. ...
... In addition to the well-known contributing factors including unhealthy diet and sedentary lifestyles [3,4], exposure to environmental chemicals such as endocrine disrupting chemicals (EDCs) has been implicated in the etiology of CVD [2,[5][6][7]. For example, the ubiquitous plastic-associated EDCs including base chemical bisphenol A (BPA) and numerous plasticizers have been associated with increased CVD risk in humans [2,[5][6][7][8][9][10][11][12][13]. While BPA has attracted considerable attention and controversy, many other plastic-associated EDCs such as phthalates are produced in high volume and can also cause adverse effects on cardiovascular health in the general population [6,7,11,[14][15][16]. ...
... For example, the ubiquitous plastic-associated EDCs including base chemical bisphenol A (BPA) and numerous plasticizers have been associated with increased CVD risk in humans [2,[5][6][7][8][9][10][11][12][13]. While BPA has attracted considerable attention and controversy, many other plastic-associated EDCs such as phthalates are produced in high volume and can also cause adverse effects on cardiovascular health in the general population [6,7,11,[14][15][16]. However, the mechanisms by which exposure to these EDCs influences CVD risk are still poorly understood, which continues to hamper rational assessment of the health risks of EDC exposure. ...
Plastic-associated endocrine disrupting chemicals (EDCs) have been implicated in the etiology of cardiovascular disease (CVD) in humans, but the underlying mechanisms remain elusive. Dicyclohexyl phthalate (DCHP) is a widely used phthalate plasticizer; whether and how exposure to DCHP elicits adverse effects in vivo is mostly unknown. We previously reported that DCHP is a potent ligand of the pregnane X receptor (PXR) which acts as a xenobiotic sensor to regulate xenobiotic metabolism. PXR also functions in macrophages to regulate atherosclerosis development in animal models. In the current study, LDL receptor-deficient mice with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) mice and their control littermates (PXRF/FLDLR−/−) were used to determine the impact of DCHP exposure on macrophage function and atherosclerosis. Chronic exposure to DCHP significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of PXRF/FLDLR−/− mice by 65% and 77%, respectively. By contrast, DCHP did not affect atherosclerosis development in PXRΔMyeLDLR−/− mice. Exposure to DCHP led to elevated expression of the scavenger receptor CD36 in macrophages and increased macrophage form cell formation in PXRF/FLDLR−/− mice. Our findings provide potential mechanisms underlying phthalate-associated CVD risk and will ultimately stimulate further investigations and mitigation of the adverse effects of plastic-associated EDCs on CVD risk in humans.
... El mecanismo está ligado con el incremento a la sensibilidad a la angiotensina II e impedimento en la vasodilatación mediada por el endotelio vascular. (Lind L Lind PM 2012). ...
... Numerosos experimentos en animales y estudios poblacionales en humanos han demostrado relación entre los perturbadores endocrinos y el riesgo de padecer DM tipo 2. El mecanismo de acción parece ser la alteración de la fisiología pancreática, afectando las células productoras de insulina y glucagón, llevando a cambios en la regulación de la glucosa y del metabolismo lipídico, por inhibición de la adiponectina, hormona que aumenta la sensibilidad a la insulina. (Lind L Lind PM 2012). . ...
... El análisis de la relación entre contaminantes orgánicos persistentes (POPs) y la diabetes mellitus, en estudios epidemiológicos a través del mundo, con meta-análisis de casos y controles en un Programa Toxicológico Nacional, Taller de Revisión (E.U. 2011), reveló una positiva asociación entre POPs con diabetes mellitus tipo 2. (Lind L Lind PM 2012) (Alonso-Magdalena P et al., 2011 (Thayer C et al., 2012) (Everet CJ et al., 2010) (Kuo CC et al., 2013) (Dirinck EL et al., 2014) (Magliano DJ et al., 2014). ...
Compromiso renal debido a la contaminación ambiental como factor coadyuvante en la gran prevalencia de la enfermedad renal crónica en el mundo
... Кардио-метаболические эффекты стойких органических поллютантов (полихлорированные бифенилы, диоксины, ароматические соединения, галогензамещенные ароматические углеводороды) (persistent organic pollutants -POPs) в научной литературе описаны крайне скудно. Для изучения биологических эффектов данных соединений на сердечно-сосудистую систему применяются преимущественно кросс-секционные популяционные и проспективные исследования, которые позволяют проследить отдалённые эффекты низких доз органических токсикантов [4]. Патогенетические механизмы действия POPs в отношении кардио-метаболических нарушений имеют мало специфических черт и представляют собой типовые патологические процессы [5]. ...
... 3. Каждый третий работник флотофабрики предприятия по производству калийных удобрений имеет признаки эндотелиальной дисфункции, преимущественно умеренной степени выраженности, связанной с повышенным уровнем формальдегида в крови и гептана в моче, при этом риск развития эндотелиальной дисфункции выше в 2,3 раза, чем в группе сравнения. 4. Снижение растяжимости сосудистой стенки, признаки эндотелиальной дисфункции свидетельствует о возрастании риска сердечно-сосудистых осложнений у работающих на предприятии по производству калийных удобрений. ...
The relevance of the work is due to the high risk of the development of production-related pathology in employees of the enterprise for the production of potash fertilizers. The study aims to assess the morphofunctional state of the arteries as an early marker of production-related pathology in employees of a potash fertilizer plant. The authors examined 160 workers engaged in the production of potash fertilizers and engaged in work with harmful working conditions (observation group). The comparison group included 82 people who were not exposed to harmful production factors in the course of their work. We conducted an analysis of working conditions, an assessment of the air quality in the work area for the content of hexane, heptane and formaldehyde. To determine the studied chemical compounds in biological media (blood, urine), the researchers used chemical-analytical methods. The scientists used ultrasound diagnostics to assess endothelium-dependent vasodilation of the brachial artery, and also used sphygmomanometry to study the stiffness of the arterial wall. There is a presence of hexane, heptane and formaldehyde in the air of the working area of the observation group. In those working in harmful working conditions, the content of formaldehyde in the blood, heptane and hexane in the urine exceeded the indicators of the comparison group by 1.2-1.5 times. 65.3% of the employees of the observation group showed a decrease in the extensibility of the vascular wall, while the risk of developing these changes in them is 1.5 times higher than the comparison group. In 29.8% of cases in the observation group, we diagnosed signs of endothelial dysfunction, mainly of moderate severity, due to increased levels of formaldehyde in the blood and heptane in the urine. The risk of developing endothelial dysfunction in workers in harmful working conditions was 2.3 times higher. The revealed violations in workers engaged in the production of potash fertilizers in the form of a decrease in the extensibility of the vascular wall and signs of endothelial dysfunction indicate the presence of additional risk factors for cardiovascular diseases.
... Recently, chronic exposure to low-dose POPs has been linked to the risk of many chronic diseases including type 2 diabetes mellitus and cardiovascular diseases in the general population 3,4 . Although high doses of individual compounds belonging to POPs are well-known mitochondrial toxins, a recent human and in vitro study demonstrated that even low-dose POPs can impair mitochondrial function through the impairment of oxidative phosphorylation 5 . ...
... In fact, serum concentrations of POPs are not determined by the recent exposure amount from external sources, but by the amount of POPs released from adipose tissue into circulation 6 . Therefore, the dynamics of POPs stored in adipose tissue are directly related to the findings on POPs from recent epidemiological studies 3,4 . ...
... Studies showed associations between occupational exposure to POPs and cardiovascular and endocrine disruptive health issues [34]. POPs have been related to poor neurobehavior and immunity, reduced Reproductive hormone secretion, diabetes, and more [35]. ...
... No form of BMAA was detected in human brain tissue from other causes of death, indicating that BMAA may be involved in the pathogenic process of amyotrophic lateral sclerosis-parkinsonism (ALS-PDC) [69]. Arsenite Interacts with lipoic acid to inhibit pyruvate dehydrogenase (PDH) in the tricarboxylic acid cycle (TCA) cycle to interfere with cellular energy metabolism [14] Arsenate Inhibits oxidative phosphorylation and energy-related NAD+ reduction during mitochondrial respiration and ATP synthesis [14] Dimethyl-arsenic compounds Promote cancer and tumor [15] Manganese Associated with hyperactivity, weakened cognitive competence, and lower intelligence quotient; associated with increased infant mortality; affects mitochondrial function; causes decreased myocardial contractility and vasodilation; causes acute reduction in blood pressure [21][22][23] Persistent organic pollutants (POPs) Alters cancer gene expression by affecting miRNAs and target genes associated with a variety of cancers; associated with cardiovascular and endocrine disrupting health problems; acts as endocrine disruptors, mimicking hormones by binding or inhibiting hormone receptors; causes mammary gland dysplasia and Inhibited ovarian maturation; causes enlarged liver cells, which may lead to hepatotoxicity, etc. [33,34,36,37] Lipid ozonation products (LOPs) ...
Climate change has become one of the biggest challenges for the 21st century. Global warming, sea level rise, changes in weather conditions, and atmospheric contamination caused by climate change not only have impacts on nature but also present threats to human health. Climate change can influence the generations and distribution of some representative toxic compounds with specific examples, including heavy metals (arsenic and manganese), persistent organic pollutants (POPs), air pollutants, and biotoxins (domoic acid and β-N-methylamino-L-alanine). This review discusses how the effects of climate change drive the production and spread of toxic substances that enter the human body through different means as well as presents the biochemical mechanisms and experimental evidence of their toxicological effect on human health, which provides an insight on climate change allowing toxic substances to enter human body and calls on readers to understand and pay attention to climate change from a more comprehensive aspect
... The rising prevalence of MetS is largely attributed to the sedentary lifestyle and the obesity epidemic afflicting the global population. However, exposure to environmental pollutants has been suggested to be an additional risk factor for the development of MetS [6,7]. These metabolism-disrupting or endocrine-disrupting chemicals (EDCs) are especially linked to the incidence of type 2 diabetes and its preceding phenomena, namely insulin resistance and prediabetes [8,9]. ...
... In addition, a closely related environmental obesogen hypothesis has been proposed suggesting a causative role for EDCs in the pathogenesis of obesity [10,11]. There are also links between exposure to EDCs and the other components of MetS, i.e., hypertension, low HDL cholesterol (HDL-C), and elevated triglycerides [7]. ...
Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesized to play an important role in metabolic disruption elicited by exposure to endocrine-disrupting chemicals. The majority of the data on the effects of PXR activation on metabolic health come from animal and cell culture experiments. However, randomized, placebo-controlled, human trials indicate that the treatment with PXR ligands impairs glucose tolerance and increases 24-h blood pressure and heart rate. In addition, plasma 4β-hydroxycholesterol (4βHC), formed under the control of PXR in the liver, is associated with lower blood pressure in healthy volunteers. Furthermore, 4βHC regulates cholesterol transporters in peripheral tissues and may activate the beneficial reverse HDL cholesterol transport. In this review, we discuss the current knowledge on the role of PXR and the PXR–4βHC axis in the regulation of components of metabolic syndrome.
... Additionally, some studies have examined environmental contaminant body burden and its association with cIMT. Carotid IMT has been shown to be positively associated with various individual contaminants, including metals [19][20][21][22], persistent organic pollutants (POPs) [23], perfluorinated compounds (PFCs) [24][25][26], and bisphenol-A and phthalates [28]. However, no studies have assessed the effects of complex xenobiotic mixtures such as persistent organic pollutants (POPs), metals, and metalloids [28]. ...
... Carotid IMT has been shown to be positively associated with various individual contaminants, including metals [19][20][21][22], persistent organic pollutants (POPs) [23], perfluorinated compounds (PFCs) [24][25][26], and bisphenol-A and phthalates [28]. However, no studies have assessed the effects of complex xenobiotic mixtures such as persistent organic pollutants (POPs), metals, and metalloids [28]. Therefore, the aim of this study was to assess the association between cIMT and complex body burden mixtures of persistent organic pollutants, metals, and metalloids using data from the Environment-and-Health Study in the Eeyou Istchee territory of Quebec, Canada. ...
Background:
The burden of cardiovascular disease (CVD) morbidity and mortality is higher among Indigenous persons, who also experience greater health disparities when compared to non-Indigenous Canadians, particularly in remote regions of Canada. Assessment of carotid intima-media thickness (cIMT), a noninvasive screening tool and can be used as biomarker to assess increased CVD risk. Few studies have examined environmental contaminant body burden and its association with cIMT.
Methods:
Data from the Environment-and-Health Study in the Eeyou Istchee territory of northern Québec, Canada was used to assess complex body burden mixtures of POPs, metals and metalloids among (n = 535) Indigenous people between 15 and 87 years of age with cIMT. First, Principal Component Analysis (PCA) was used to reduce the complexity of the contaminant data. Second, based on the underlying PCA profiles from the biological data, we examined each of the prominent principal component (PC) axes on cIMT using multivariable linear regression models. Lastly, based on these PC axes, cIMT was also regressed on summed (Σ) organic compound concentrations, polychlorinated biphenyl, perfluorinated compounds, respectively, ∑10 OCs, ∑13 PCBs, ∑3PFCs, and nickel.
Results:
Most organochlorines and PFCs loaded primarily on PC-1 (53% variation). Nickel, selenium, and cadmium were found to load on PC-5. Carotid-IMT was significantly associated with PC-1 β = 0.004 (95 % CI 0.001, 0.007), and PC-5 β = 0.013 (95 % CI 0.002, 0.023). However, the association appears to be greater for PC-5, accounting for 3% of the variation, and mostly represented by nickel. Results show that that both nickel, and ∑3PFCs were similarly associated with cIMT β = 0.001 (95 % CI 0.0003, 0.003), and β = 0.001 (95 % CI 0.0004, 0.002), respectively. But ∑10OCs was significantly associated with a slightly greater β = 0.004 (95 % CI 0.001, 0.007) cIMT change, though with less precision. Lastly, ∑13PCBs also increased β = 0.002 (95 % CI 0.0004, 0.003) cIMT after fully adjusting for covariates.
Conclusion:
Our results suggest that environmental contaminants are associated with cIMT. This is important for the Cree from the Eeyou Istchee territory who may experience higher body burdens of contaminants than non-Indigenous Canadians.
... After the title reading, 62 studies were excluded, and 17 were retained for abstract and/or full text reading. Of these, 11 were excluded for the following reasons (Supplemental table 1): 5 were reviews (Mariana and Cairrao, 2020;Lind and Lind, 2012;Chang et al., 2021;Monica Lind and Lind, 2020;Mariana et al., 2016), 1 evaluated the exposure and the outcome in different participants 10 years apart (phthalate exposure during pregnancy and the carotid intima-media thickness in children at the age of 10) (Blaauwendraad et al., 2022), 1 biomonitoring study on phthalates in mother-child pairs but the association with atherosclerosis was not considered (Carli et al., 2022), 1 animal study (Jaimes et al., 2017), and 3 studies evaluating other outcomes, such as CVD in the general population (Zhu et al., 2021), insulin resistance and endothelial dysfunction in children (Kataria et al., 2017), and coronary heart disease and atherothrombotic biomarkers (Su et al., 2019a). Finally, 6 studies were included in this systematic review (Lind and Lind, 2011;Wiberg et al., 2014;Su et al., 2019b;Lin et al., 2020;Zhang et al., 2021;Yalçin et al., 2022) (Table 1). ...
Phthalates may be associated with an increased risk of cardiometabolic diseases by interfering with glucose and lipid metabolism and by promoting adipogenesis. This study aimed to perform a systematic review and meta-analysis of the association between phthalate exposure and subclinical carotid atherosclerosis, using surrogate markers such as carotid intima-media thickness (IMT) and carotid plaques. The literature search was performed using four databases (Web of Science, Medline, PubMed, and Scopus), and this systematic review includes all available observational studies until July 6th, 2023. The Joanna Briggs Institute critical appraisal tool was used to assess the risk of bias. Meta-analyses were performed, and random effects models were used. Six high-quality cross-sectional studies and 2,570 participants aged 12 to 70 were included. Six phthalate metabolites showed significant associations with subclinical carotid atherosclerosis. Exposure to MBzP, ΣDEHP, and MnBP was associated with increased carotid IMT. Exposure to MEP was associated with a higher prevalence of carotid plaques, and MiBP was associated with a lower prevalence. Mixed results were observed for MMP in older adults. The meta-analyses showed a high degree of heterogeneity, and the results are based on single studies. This study accurately describes the evidence of this association to date, suggesting that phthalates are associated with increased carotid IMT and a higher prevalence of carotid plaques. Further research is needed to elucidate this association, as phthalates are still used in the manufacture of everyday products, humans continue to be exposed to them, and atherosclerosis is a public health concern.
... Objective This protocol sets out the development of a methodological stepby-step framework for a systematic mapping review that aims to characterize and analyze the cardiotoxic potential of environmental pollutants. Evidence maps and knowledge graphs will il-ants such as particulate matter (Du et al., 2016), pesticides (Georgiadis et al., 2018), heavy metals (Agarwal et al., 2011), bisphenol A (Lang et al., 2008;Melzer et al., 2010Melzer et al., , 2012, polycyclic aromatic hydrocarbons (Clark et al., 2012), nanoparticles (Donaldson et al., 2013), and persistent organic pollutants (Lind and Lind, 2012) to CVD outcomes including hypertension, coronary heart disease, stroke, and heart failure (Burroughs Peña and Rollins, 2017;GBD 2019Risk Factors Collaborators, 2020). ...
An increasing body of evidence identifies pollutant exposure as a risk factor for cardiovascular disease (CVD), while CVD incidence rises steadily with the aging population. Although numerous experimental studies are now available, the mechanisms through which lifetime exposure to environmental pollutants can result in CVD are not fully understood. To comprehensively describe and understand the pathways through which pollutant exposure leads to cardiotoxicity, a systematic mapping review of the available toxicological evidence is needed. This protocol outlines a step-by-step framework for conducting this review. Using the National Toxicology Program (NTP) Health Assessment and Translation (HAT) approach for conducting toxicological systematic reviews, we selected 362 out of 8111 in vitro (17%), in vivo (67%), and combined (16%) studies for 129 potential cardiotoxic environmental pollutants, including heavy metals (29%), air pollutants (16%), pesticides (27%), and other chemicals (28%). The internal validity of included studies is being assessed with HAT and SYRCLE Risk of Bias tools. Tabular templates are being used to extract key study elements regarding study setup, methodology, techniques, and (qualitative and quantitative) outcomes. Subsequent synthesis will consist of an explorative meta-analysis of possible pollutant-related cardiotoxicity. Evidence maps and interactive knowledge graphs will illustrate evidence streams, cardiotoxic effects and associated quality of evidence, helping researchers and regulators to efficiently identify pollutants of interest. The evidence will be integrated in novel Adverse Outcome Pathways to facilitate regulatory acceptance of non-animal methods for cardiotoxicity testing. The current article describes the progress of the steps made in the systematic mapping review process.
... Due to environmental pollution caused by these chemicals, living organisms that are exposed to them, have health problems such as diabetes mellitus, obesity, cardiovascular disease, and liver damage in terms of human health 5,6 . In recent years, interest in environmental endocrine disruptors (EEDs) such as NP is increasing and recent studies have indicated that environmental exposure causes cardiovascular diseases to be accepted as epidemiological diseases, and NP is closely related to the occurrence and progression of it [7][8][9][10] . ...
We are exposed to Nonylphenol which is an endocrine disrupting chemical used in the plastic industry, in our daily life without realizing it. The aim of this study was to evaluate the effect of Nonylphenol (NP) on heart tissue and the protectiveness of melatonin treatment on the heart damage with histopathological and immunohistological parameters. Twenty-one female rats were randomly divided into three groups: Control, NP, and Melatonin+NP. Heart tissues were removed two weeks later in all groups. Histopathological evaluation was performed with Hematoxylin&Eosin staining. IL-1β, IL-6, and Caspase-3 expression in heart tissues were detected immunohistochemically. Melatonin had a protective effect on heart tissue against NP-induced histopathological changes such as necrosis, hemorrhage, and inflammation. According to our results, the immunoreactivity intensity of inflammation markers such as IL-1β and IL-6 was significantly lower in the Melatonin+NP group than in the NP group. Finally, we investigated the pro-apoptotic marker caspase-3 immunoreactivity, which may explain the apoptotic effects of NP on the heart. According to our findings, melatonin significantly reduced the caspase-3 expression induced by NP. Our results showed that pretreatment with melatonin is beneficial to protect from NP-induced heart damage. These findings reinforce the protective effects of melatonin on heart tissue and more clinical studies are needed.
... P-int indicates the P values of the modifying effects of AMED score. Abbreviations: HTN, hypertension; PM 2.5 , fine particulate matter; IQR, interquartile range; AMED, alternative Mediterranean diet respiratory tract and cause oxidative stress and systemic inflammatory responses, which may lead to increased sympathetic nerves, affect hemodynamic responses, arterial remodeling, endothelial dysfunction, and thrombosis [55][56][57][58][59][60][61]. When these reactions are repeated, they may lead to increased total peripheral resistance and increased blood pressure [62]. ...
Background
Studies have shown that nutritional supplements could reduce the adverse effects induced by air pollution. However, whether dietary patterns can modify the association of long-term exposure to fine particulate matter (PM2.5) and its constituents with hypertension defined by the 2017 ACC/AHA guideline has not been evaluated.
Methods
We included 47,501 Chinese adults from a nationwide cross-sectional study. PM2.5 and five constituents were estimated by satellite-based random forest models. Dietary approaches to stop hypertension (DASH) and alternative Mediterranean diet (AMED) scores were calculated for each participant. Interactions between dietary patterns and air pollution were examined by adding a multiplicative interaction term to logistic models.
Results
Long-term exposure to PM2.5 and its constituents was associated with an increased risk of hypertension and stage 1–2 hypertension. The DASH and AMED scores significantly modified these associations, as individuals with higher scores had a significantly lower risk of air pollution-related hypertension and stage 1–2 hypertension (P-interaction < 0.05), except for interaction between PM2.5, sulfate, nitrate, ammonium, and AMED score on stage 1 hypertension. For each IQR increase in PM2.5, participants with the lowest DASH and AMED quintiles had hypertension risk with ORs (95%CI) of 1.20 (1.10, 1.30) and 1.19 (1.09, 1.29), whereas those with the highest DASH and AMED quintiles had lower risks with 0.98 (0.91, 1.05) and 1.04 (0.97, 1.11). The stratified analysis found modification effect was more prominent in the < 65 years age group. Consuming more fresh vegetables, fruits, whole grains, and dairy would reduce the risk of hypertension caused by PM2.5 and its constituents.
Conclusions
Dietary patterns rich in antioxidants can reduce long-term exposure to PM2.5 and its constituents-induced hypertension defined by the 2017 ACC/AHA guideline, especially in young and middle-aged individuals. Compared to the Mediterranean diet, the DASH diet offers superior dietary guidance to prevent stage 1 hypertension caused by air pollution.
... As expected, smoking cessation improves CEC and increases HDL anti-inflammatory function [119]. Recently, plastic-associated chemicals, including bisphenol A (BPA) and phthalates, have been the focus of research owing to their atherogenicity [120]. In particular, BPA is associated with atherosclerosis [121][122][123] and exerts proinflammatory effects [124]. ...
Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials.
... The most commonly used are: di-ethylhexyl phthalate (DEHP), di-isodecyl phthalate (DIDP) and di-isononyl phthalate (DINP) [3,4]. Phthalates are toxic substances that compromise immune function, the endocrine and reproductive systems, neural and physical development, as well as the increased risk of cardiovascular disease [5][6][7]. ...
The aim of this work is to study the influence of the weathering conditions on the degradation level of stabilized PVC. Epoxidized Sunflower oil (ESO) was used as a new biodegradable stabilizer for PVC. Flexible plasticized formulations (40% plasticizer) were realized, the natural weathering of the PVC samples was investigated. The samples were exposed in Tizi Ouzou (Algeria) for nine months. The samples were characterized by Fourier transform infrared spectroscopy in order to follow the structural changes. Moreover, the variation of the mass of the samples, the variation of density and mechanical properties (tensile and shore D hardness) were taken into account. Samples were characterized in terms of morphology by SEM. The best results were obtained with the formulation containing DINA and ESO compared to the traditional formulation containing DOP and ESO.
... A common thread linking these diseases is a change in hemodynamics connected to ischemic injury [180][181][182], a factor that independently drives LUTD in mice [174]. Environmental chemical exposures have been linked to cardiovascular disease and diabetes [183][184][185][186], and this is another mechanism by which they may drive LUTD. ...
Lower urinary tract dysfunction (LUTD) is nearly ubiquitous in men of advancing age and exerts substantial physical, mental, social, and financial costs to society. While a large body of research is focused on the molecular, genetic, and epigenetic underpinnings of the disease, little research has been dedicated to the influence of environmental chemicals on disease initiation, progression, or severity. Despite a few recent studies indicating a potential developmental origin of male LUTD linked to chemical exposures in the womb, it remains a grossly understudied endpoint in toxicology research. Therefore, we direct this review to toxicologists who are considering male LUTD as a new aspect of chemical toxicity studies. We focus on the LUTD disease process in men, as well as in the male mouse as a leading research model. To introduce the disease process, we describe the physiology of the male lower urinary tract and the cellular composition of lower urinary tract tissues. We discuss known and suspected mechanisms of male LUTD and examples of environmental chemicals acting through these mechanisms to contribute to LUTD. We also describe mouse models of LUTD and endpoints to diagnose, characterize, and quantify LUTD in men and mice.
... Williams and Hare 2011). The genetically linked defect of β-cell function can involve a mutation of the four 4α hepatocyte nuclear transcription factor, the 1α hepatocyte, the insulin promoter, or the genetic defect at the insulin secretion(Herder and Roden 2011);(Lind and Lind 2012) . ...
Obesity is a main public health problem. It is frequently described as a
disorder of irregular or extreme fat accumulation in adipose tissues. It is
caused by a mixture of excessive nutrition intake, lack of bodily activity and
genetic defenselessness. An insufficient cases are caused principally by
genetic factor, endocrine complaints, medicines or psychological disorders. In
Iraq, the occurrence of T2DM in obese persons is increasing and shows a
great load on the public health and socioeconomic growth.
The current study aims to measure some cytokines related to obesity
including Lipocalin-2 and Adipolin in control individuals, diabetic obese
individuals and diabetic non obese patients. Further; the study involved
estimated serum levels of Malondialdehyde(MDA), Total Antioxidants
Capacity (TAC) and Total Oxidant Status (TOS) and to find out a possible
relationship between these markers and other parameters also estimated such
as; BMI, FBS, and lipid profiles.
The case-control study design consists of 27 diabetic obese patients and
27 diabetic nonobese patients (they were selected from Center for Diabetes
and Endocrinology of Hilla District, Babylon, Iraq, Marjan Teaching
Hospital)18 obese control and 18 nonobese control. The four groups are not
matched for age. FSG, Malondialdehyde (MDA), lipid profile, Total
Antioxidants Capacity (TAC), Total Oxidant Status (TOS) are determined by
colorimetric method. While Lipocalin-2 and Adipolin are measured in sera by
(ELISA) technique.
... During the last decade, major metabolic diseases such as diabetes and cardiovascular disease have been increasingly associated with exposure to persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), dioxins and pesticides (Lind and Lind, 2012). For example, an increased risk of T2D has been found to relate to exposure to PCBs, PBDEs, and/or organochlorine pesticides including dichlorodiphenyldichloroethylene (DDE), heptachlor, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), trans-nonachlor or chlordane (Turyk et al., 2009;Grandjean et al., 2011;Evangelou et al., 2016;Wolf et al., 2019;Cordier et al., 2020). ...
Humans are exposed to an ever-increasing number of environmental toxicants, some of which have gradually been elucidated to be important risk factors for metabolic diseases, such as diabetes and obesity. These metabolism-sensitive diseases typically occur when key metabolic and signaling pathways were disrupted, which can be influenced by the exposure to contaminants such as endocrine disrupting chemicals (EDCs), along with genetic and lifestyle factors. This promotes the concept and research on environmental metabolism disrupting chemicals (MDCs). In addition, identifying endogenous biochemical markers of effect linked to disease states is becoming an important tool to screen the biological targets following environmental contaminant exposure, as well as to provide an overview of toxicity risk assessment. As such, the current review aims to contribute to the further understanding of exposome and human health and disease by characterizing environmental exposure and effect metabolic biomarkers. We summarized MDC-associated metabolic biomarkers in laboratory animal and human cohort studies using high throughput targeted and nontargeted metabolomics techniques. Contaminants including heavy metals and organohalogen compounds, especially EDCs, have been repetitively associated with metabolic disorders, whereas emerging contaminants such as perfluoroalkyl substances and microplastics have also been found to disrupt metabolism. In addition, we found major limitations in the effective identification of metabolic biomarkers especially in human studies, toxicological research on the mixed effect of environmental exposure has also been insufficient compared to the research on single chemicals. Thus, it is timely to call for research efforts dedicated to the study of combined effect and metabolic alterations for the better assessment of exposomic toxicology and health risks. Moreover, advanced computational and prediction tools, further validation of metabolic biomarkers, as well as systematic and integrative investigations are also needed in order to reliably identify novel biomarkers and elucidate toxicity mechanisms, and to further utilize exposome and metabolome profiling in public health and safety management.
... Similarly 50% increase LDL-C level found in younger and 685 in both middle and older persons. Previous studies reported that the nature of POPs are lipid soluble so these compounds regulate lipid and increase lipid weight but in the case of a cardiovascular disorder in contrast to the above statement numerous research on animal and human beings show lipid alteration due to these toxic pollutants (Lind and Lind, 2012,). ...
This study determines the associations among serum lipid profiles, risk of cardiovascular disease, and persistent organic pollutants. Using Gas chromatography technique, the intensity of toxic pollutant residues in serum samples of Hypertensive patients were measured. Based on statistical analysis, the effects of different covariates namely pesticides, age, systolic blood pressure, diastolic blood pressure, and lipid profile duration was checked using the logistic regression model. Statistical computation was performed on SPSS 22.0. The P-values of F-Statistic for each lipid profile class are greater than 0.01 (1%), therefore we cannot reject the null hypothesis for all cases. The estimated coefficients, their standard errors, Wald Statistic, and odds ratio of the binary logistic regression model for different lipid profile parameters indicate if pesticides increase then the logit value of different lipid profile parameters changes from -0.46 to -0.246 except LDL which increases by 0.135. The study reports a significantly increased threat of cardiovascular disease with increased concentrations of toxic pollutants.
... Multiple factors including environmental and chemical exposures contribute to CVDs. Evidences from epidemiological, in vitro and in vivo studies relate the CVDs with PCBs present in the environment [38]. It has also been reported that there is a dose-dependent relationship between the serum levels of PCBs concentrations and CVDs [39]. ...
Polychlorinated biphenyls (PCBs) are industrially synthesized compounds that can produce hazardous reactions and diseases in human beings. They can cause multiple toxic effects in human beings ranging from mild effects such as some behavioural changes to severe effects such as neurotoxic reactions. Humans can be exposed to these PCBs in multiple ways such as combustion and burning of coal or wood or either via accidental exposure, for instance fire in buildings. PCBs are one of the most studied pollutants in the environment and have various congeners that differ from one another in positions and numbers of chlorine atoms. Metabolism of these PCBs occurs via cytochrome P450 mediated transformation that depends on their structural properties. There are many uncertainties in assessing PCBs-associated health risks as it involves a number of extrapolations and each extrapolation introduces uncertainty in the risk assessment. According to the mechanism of toxicity, the toxic congeners cause adverse effects at cellular level including effects on intracellular absorption, cell membrane, gap junctions and neurotoxic effects. Epidemiological studies suggest that nutrition and exercise can play a major role in the prevention and protection of human beings from the potential adverse health effects of PCBs.
... More than 36 genes attribute to the occurrence of DM . It represents about ten percent of chance of occurrence of DM (17,18). ...
Background: diabetes mellitus (T2DM) is a metabolic problem characterized by hyperglycemia. It arises from impaired insulin action, impaired insulin secretion or both and it is frequently associated with insulin resistance (IR) (Crook, 2012). The prevalence of T2DM is rapidly increasing, with consequent concomitant of the rise of numerous health medical problems due to chronic complications (Preeti & Malani, 2012).. Aim: To evaluate the association of micro and macro vascular complication with the occurrence and prognosis of T2DM as well as the hyperlipidemia. Methods: A case–control study of 120 individuals (60 diabetic patients and 60 apparently healthy individuals) were non randomly selected. The work was carried out at Al-Sader medical city from Oct 2017 to march 2018. Data collection was obtained from the direct meeting with the patient by the research staff and documentation section in the diabetic center at al Sader medical city from October 2017 till march 2017. Volunteer data was obtained from the healthy individuals of the patient relatives, medical staff, close friends and family. Results: Data showed that diabetic patient had more macro and micro vascular complications than healthy volunteer , also diabetic patients type one showed more retinal, renal ,cardiac, neural complication than type two. Retinopathy is progressed in type one and even lead to visual problems than type two and these patients also suffered more from renal complication and gangrene occurrence than type two diabetes. Ignorance of intake of medication is number one in the reasons of low compliance and the bad prognosis of the patient of the patient is mostly due to the un preferred injectable dosage form.
Keyword: diabetes,macro,micro
... In addition to visual pollution, this waste can interact with the environment and release some of the additives present (Haider and Karlsson 1999). Phthalates are toxicants for jeopardizing immune function, endocrine and reproductive systems, neural and physical development and increase risk of cardiovascular disease (Lind and Lind 2012;Ejaredar et al. 2015;Trasande et al. 2013). DEHP affects males and females fertility and causes severe testicular alterations (testicular atrophy with the possibility of complete absence of spermatogenesis (Gray et al. 2000;Calafat et al. 2006). ...
The aim of this paper is the determination of the migration and biodegradation of the PVC additives in the soil. Epoxidized Sunflower Oil (ESO) was used as a thermal organic co-stabilizer for PVC; it was obtained by epoxidation of commercial sunflower oil. Two plasticizers were used: dioctyl phthalate (DOP) and diisononyl adipate (DINA). A natural aging test on site in a garden soil (Tizi Ouzou, Algeria) of the PVC samples was investigated for 6 months. The samples were characterized by Fourier transform infrared (FTIR).The morphological changes were followed by scanning electron microscopy (SEM). The evolution of the bacterial growth, identification using biochemical tests, variation of pH and variation of mass were investigated. The results showed that the nature of the plasticizer and heat stabilizer affects the properties of PVC as well as the phenomena of migration and biodegradation.
... Environmental toxicology research can provide an understanding of how these chemical exposures influence human health. Of all the chemical exposures that individuals experience, phthalate and bisphenol chemicals have emerged as two potential contributors to cardiovascular dysfunction Han & Hong, 2016;Lind & Lind, 2012;Mariana, Feiteiro, Verde, & Cairrao, 2016;. Phthalates and bisphenols are high production volume chemicals that are widely used in the manufacturing of consumer and medical-grade plastics. ...
Phthalates and bisphenols are high production volume chemicals that are used in the manufacturing of consumer and medical products. Given the ubiquity of bisphenol and phthalate chemicals in the environment, biomonitoring studies routinely detect these chemicals in 75–90% of the general population. Accumulating evidence suggests that such chemical exposures may influence human health outcomes, including cardiovascular health. These associations are particularly worrisome for sensitive populations, including fetal, infant and pediatric groups—with underdeveloped metabolic capabilities and developing organ systems. In the presented article, we aimed to review the literature on environmental and clinical exposures to bisphenols and phthalates, highlight experimental work that suggests that these chemicals may exert a negative influence on cardiovascular health, and emphasize areas of concern that relate to vulnerable pediatric groups. Gaps in our current knowledge are also discussed, so that future endeavors may resolve the relationship between chemical exposures and the impact on pediatric cardiovascular physiology.
... In one population-based human study, levels of BPA and several phthalate metabolites were associated with lipid infiltration of the vascular wall and therefore suggesting that these chemicals play a role in atherosclerosis (Lind and Lind 2011). Furthermore, BPA was reported to be positively associated with cardiovascular disease and prevalent myocardial infarction in a cross-sectional analysis of 1455 adults (Lind and Lind 2012). ...
In a recent scenario bio-plastics are expected to change the image of the petroleum-based plastics as they are presenting solutions for waste problems and contributing the environment sustainability. Bio-plastics are intracellular polymers that are synthesized by the bacteria in the situations where there is nutrient depletion of some essential elements. Due to their biodegradability and environment-friendly nature, bio-plastics have outshined the conventional petrochemical-based plastics and, hence, have captured the attention of both the researchers and the industrialists since the last few decades. The only drawback of these bio-plastics is the cost of their production, but the researchers in the recent years have been successful in producing different bio-plastics from the different waste materials such as agro-industrial wastes and activated sludge. In this way the production of bio-plastics acts in two ways: firstly, they can terminate the use of non-biodegradable petrochemical plastics, and, secondly, by their production we can transform the different hazardous wastes into bio-plastics. Industrial, agriculture and dairy wastes are rich in carbon content. This chapter provides detailed information about classification waste materials to be used as carbon sources for different metabolic pathways. It also deals with different techniques to convert these wastes to produce bio-plastics using indigenous bacteria.
... 3,5 Few epidemiological and experimental data have shown that exposure to these pollutants leads to increased cardiovascular morbidity and mortality. 6,7 Evidence has shown that obesity-induced macrophage accumulation in adipose tissue and the artery wall is exacerbated by dietary cholesterol, and these local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation, and increased atherosclerosis in mouse models as well as in human patients. 8,9 Recent studies also point to several pro-inflammatory cytokines, reactive oxygen species (ROS), and free fatty acid intermediates that might play an even greater role in regulating a series of intracellular signaling pathways, sustaining as well as perpetuating the development of the MetS and its cardiovascular disease complications. ...
Artificial environmental endocrine disrupting chemicals (EDCs) exert public health concerns. Exposure to EDCs may induce various disorders in the cardiometabolic system. However, the underlying mechanisms remain largely unknown. Over the last decade, an abundance of evidence has emerged demonstrating a close link between cardiometabolic disorders and inflammation. The aim of the present study was to evaluate the immunological effects on macrophages from six EDCs via sirtuin (SIRT) regulation using the murine macrophage RAW 264.7 cell. We studied first the effects of these EDCs, including a series of doses of benzyl butyl phthalate (BBP), bisphenol A (BPA), diethylhexyl phthalate (DEHP), mono-(2-ethylhexyl)phthalate (MEHP), perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS), on SIRT1-7 transcriptional level. Among these EDCs, MEHP significantly decreased all sirtuin genes’ expression in a dose-dependent manner. Under MEHP treatment, SIRT activity and protein expression were significantly decreased, while the protein expression of acetylated NF-κB was significantly increased along with significant increases in ΙL-1β transcription. These results indicate that MEHP may induce the inflammatory response via SIRT mediated acetylation of NF-κB. Additionally, the enhanced ΙL-1β secretion in the presence of 50 μM MEHP (P < 0.01) also supports inflammasome activation (significant ASC and NLRP3 protein augmentation). Both events may be regulated by MEHP induced reactive oxygen species (P < 0.01). In conclusion, our study suggests for the first time that EDCs differentially modulate sirtuins’ gene expression levels in macrophages and that a specific phthalate MEHP can lead to an increased inflammatory response by impairing vital epigenetic regulators and inflammasome activation.
... Heart and vascular systems are highly vulnerable to a number of environmental agents such as ambient air pollution (either indoor or outdoor), heavy metals, and/or persistent organic pollutants (POPs). For example, polychlorinated biphenyls, dioxins, and pesticides (especially via the food chain) are widespread and the most extensively studied (Lind and Lind, 2012;Cosselman et al., 2015;Kaufman et al., 2016;Oikonomou et al., 2016;Bhatnagar, 2017). Like traditional risk factors (e.g., smoking and diabetes mellitus), these exposures induce chronic diseases via augmentation and/or initiation of pathophysiological processes associated with CVDs, including genetic, hemodynamic, metabolic, oxidative, and inflammation parameters related to blood-pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis. ...
Diseases are complex multifactorial processes that occur due to several external factors and/or various underlying internal biochemical and cellular processes. In this chapter, the fine balance between health and disease is discussed with a particular focus on cardiovascular diseases (CVD). CVD are the leading cause of death in developed and Westernized developing countries. A number of environmental, genetic, nutritional, and lifestyle factors have been linked to our health, especially in relation to CVD. These modifiable risk factors may cause or prevent premature mortality. Over the last few decades, with the advancement of industry and technology toward the improvement of food and drug production, medicine, and other anthropogenic activities, amenities have become more available to developed and developing societies. This often leads toward advancement, but does so sometimes to the detriment of human health. With worldwide human advancement, unforeseen challenges that can affect our health have arisen, such as ambient air pollution and contamination of ecosystems, water resources, and food chains. Consequently, sustainable development has been highlighted as a means to moderate the impact of environmental pollution on human health. However, other challenges such as nutrition and lifestyle can be key modifiable factors with a crucial role in health outcomes, especially in CVD. In this chapter, such factors are deliberated at length in relation to existing and emerging public hazards with reference to chronic diseases such as CVD.
... Fish intake was positively correlated with erythrocyte mercury content and EPA + DHA [11]. Both persistent organic pollutants and organic mercury are potential risk factors for CVD and stroke [26,27]. Daneshmand even found that higher serum omega-3 PUFA concentration was associated with an increased risk of ischaemic stroke among participants with hair mercury content above the median [28]. ...
Background
Fish intake has been postulated to reduce the risk of stroke. However, whether the beneficial effect of fish are mainly linked to fat content, as a source of omega-3 polyunsaturated fatty acids, remains unclear. We conducted a meta-analysis to compare the effect of fatty and lean fish intake on stroke risk.
Methods
We performed a literature search on four database (PubMed, Embase, Scopus, and Cochrane Library) through February 1, 2018 to identify prospective studies of fatty and lean fish in relation to stroke risk. A random-effects model was used to calculate the summary estimates.
Results
We identified five prospective studies, including 7 comparisons for fatty fish intake and 5 comparisons for lean fish intake. Compared with the highest category of intake with lowest category, the summary relative risk was 0.88 [95% confidence interval (CI), 0.74–1.04] for fatty fish intake and 0.81 (95% CI, 0.67–0.99) for lean fish intake. No heterogeneity across studies and publication bias were observed.
Conclusion
Our findings demonstrated that fatty and lean fish intake has beneficial effects on stroke risk, especially lean fish intake. Additional prospective studies are necessary to confirm these observations.
Cardiometabolic health is complex and characterized by an ensemble of correlated and/or co-occurring conditions including obesity, dyslipidemia, hypertension, and diabetes mellitus. It is affected by social, lifestyle, and environmental factors, which in-turn exhibit complex correlation patterns. To account for the complexity of (i) exposure profiles and (ii) health outcomes, we propose to use a multitrait Bayesian variable selection approach and identify a sparse set of exposures jointly explanatory of the complex cardiometabolic health status. Using data from a subset (N = 941 participants) of the nutrition, environment, and cardiovascular health (NESCAV) study, we evaluated the link between measurements of the cumulative exposure to (N = 33) pollutants derived from hair and cardiometabolic health as proxied by up to nine measured traits. Our multitrait analysis showed increased statistical power, compared to single-trait analyses, to detect subtle contributions of exposures to a set of clinical phenotypes, while providing parsimonious results with improved interpretability. We identified six exposures that were jointly explanatory of cardiometabolic health as modeled by six complementary traits, of which, we identified strong associations between hexachlorobenzene and trifluralin exposure and adverse cardiometabolic health, including traits of obesity, dyslipidemia, and hypertension. This supports the use of this type of approach for the joint modeling, in an exposome context, of correlated exposures in relation to complex and multifaceted outcomes.
The impact of micro plastics (MPs) on the bivalve larvae at different developmental stages throughout their life history, especially for the metamorphic stage is not at all available. In organisms, consequences of plastic ingestion include exposure to environmental pollutants and toxin accumulation, causing endocrine disruption, inflammatory and physiological stress. The transfer of micro plastics has been shown to transfer across food webs, however, the micro plastic accumulations across terrestrial food webs have examined but it has limited studies only. The different type of micro plastic exposure, exposure time, as well as physiological and behavioral differences among organisms exposed to micro plastics can show some of these differences in effects. If the organism ingested by the micro plastics, its interact within the gastrointestinal tracts differently in terms of the anatomy and structure of the tract, its mechanical action, transit time and chemical enzymatic action. Further, the characteristics of micro plastics such as size, shape, solubility, and surface properties also play an important role in the toxicity of micro plastics. Micro plastic pollution in the soils harms the fitness of multiple soil organisms, animals and birds underscoring the ecological risk posed by micro plastics within terrestrial ecosystems.
Exposure to ubiquitous plastic-associated endocrine disrupting chemicals (EDCs) is associated with the increased risk of many chronic diseases. For example, phthalate exposure is associated with cardiometabolic mortality in humans, with societal costs ∼ $39 billion/year or more. We recently demonstrated that several widely used plastic-associated EDCs increase cardiometabolic disease in appropriate mouse models. In addition to affecting adult health, parental exposure to EDCs has also been shown to cause metabolic disorders, including obesity and diabetes, in the offspring. While most studies have focused on the impact of maternal EDC exposure on the offspring’s health, little is known about the effects of paternal EDC exposure. In the current study, we investigated the adverse impact of paternal exposure to a ubiquitous but understudied phthalate, dicyclohexyl phthalate (DCHP) on the metabolic health of F1 and F2 offspring in mice. Paternal DCHP exposure led to exacerbated insulin resistance and impaired insulin signaling in F1 offspring without affecting diet-induced obesity. We previously showed that sperm small non-coding RNAs including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs) contribute to the intergenerational transmission of paternally acquired metabolic disorders. Using a novel PANDORA-seq, we revealed that DCHP exposure can lead to sperm tsRNA/rsRNA landscape changes that were undetected by traditional RNA-seq, which may contribute to DCHP-elicited adverse effects. Lastly, we found that paternal DCHP can also cause sex-specific transgenerational adverse effects in F2 offspring and elicited glucose intolerance in female F2 descendants. Our results suggest that exposure to endocrine disrupting phthalates may have intergenerational and transgenerational adverse effects on the metabolic health of their offspring. These findings increase our understanding of the etiology of chronic human diseases originating from chemical-elicited intergenerational and transgenerational effects.
Aging is a phenomenon in which the body's physiological and psychological adaptability to the environment gradually decreases and tends to total loss. The hallmarks of aging include genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Aging is an independent risk factor for many chronic disorders, such as cardiovascular diseases, malignant neoplasms and neurological diseases. In contrast, various diseases, genetic defects, poor lifestyle choices, environmental exposures, psychosocial stress and depression are known factors accelerating aging and thus could be intervention targets against aging and/or aging-related disorders.
Acute exposure to air pollution is associated with an increasing risk of death and cardiovascular disorders. Nonetheless, the impact of chronic exposure to air pollution on the circulatory system is still debated. Here, we review the links of chronic exposure to outdoor air pollution with mortality and most common cardiovascular diseases, in particular during the coronavirus disease 2019 event (COVID-19). We found that recent studies provide robust evidence for a causal effect of chronic exposure to air pollution and cardiovascular mortality. In terms of mortality, the strongest relationship was noted for fine particulate matter, nitrogen dioxide, and ozone. There is also increasing evidence showing that exposure to air pollution, mainly fine particulate matter and nitrogen dioxide, is associated with the development of atherosclerosis, hypertension, stroke, and heart failure. However, available scientific evidence is not strong enough to support associations with cardiac arrhythmias and coagulation disturbances. Noteworthy, for some pollutants, the risk of negative health effects is high for concentrations lower than the limit values recommended by the European Union and Word Health Organization. Efforts to diminish exposure to air pollution and to design optimal methods of air pollution reduction should be urgently intensified and supported by effective legislation and interdisciplinary cooperation.
Background
It has been suggested that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors with a potential to influence fat mass.
Objective
The primary hypothesis tested was that we would find positive relationships for PFAS vs measures of adiposity.
Methods
In 321 subjects all aged 50 years in the POEM study, five PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA)) were measured in serum together with a Dual-energy X-ray absorptiometry (DXA) scan for determination of fat and lean mass. Whole-body magnetic resonance imaging scan was performed and the body was divided into >1 million voxels. Voxel-wise statistical analysis was carried out by a novel method denoted Imiomics.
Results
PFOS and PFHxS, did not show any consistent associations with body composition. However, PFOA, and especially PFNA and PFDA, levels were inversely related to most traditional measures reflecting the amount of fat in women, but not in men. In the Imiomics analysis of tissue volume, PFDA and PFNA levels were inversely related to the volume of subcutaneous fat, mainly in the arm, trunk and hip regions in women, while no such clear relationship was seen in men. Also, the visceral fat content of the liver, the pericardium, and the gluteus muscle were inversely related to PFDA and PFNA in women.
Discussion
Contrary to our hypothesis, some PFAS showed inverse relationships vs measurements of adiposity.
Conclusion
PFOS and PFHxS levels in plasma did not show any consistent associations with body composition, but PFOA, and especially PFNA and PFDA were inversely related to multiple measures reflecting the amount of fat, but in women only.
Background:
Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo.
Objective:
We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors.
Methods:
Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD.
Results:
DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings.
Discussion:
Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs. https://doi.org/10.1289/EHP9262.
Background:
The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches.
Objectives:
We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them.
Methods:
An expert working group was convened to discuss mechanisms associated with CV toxicity.
Results:
The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling.
Discussion:
These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321.
We developed phospho-ERK1/2 ELISA for human and rainbow trout liver cells, employing HepG2 and RTL-W1 cell lines as models. The assay was applied to detect changes in ERK1/2 activity for nine chemicals, added over a wide concentration range and time points. Cell viability was measured to separate ERK1/2 regulation from cytotoxicity. Perfluorooctane sulfonate and carbendazim did not change ERK1/2 activity; influence on ERK1/2 due to cytotoxicity was indicated for tributyltin and cypermethrin. Mancozeb, benzo[a]pyrene, and bisphenol A stimulated ERK1/2 up to ∼2- (HepG2) and 1.5 (RTL-W1)-fold, though the kinetics differed between chemicals and cell lines. Bisphenol A and benzo[a]pyrene were the most potent concentration-wise, altering ERK1/2 activity in pM (HepG2) to nM (RTL-W1) range. While atrazine and ibuprofen increased ERK1/2 activity by ∼2-fold in HepG2, they did not initiate an appreciable response in RTL-W1. This assay proved to be a sensitive, medium- to high-throughput tool for detecting unrecognized ERK1/2-disrupting chemicals.
Although there are not any direct studies linking persistent organic pollutants (POPs) accumulated on marine debris to human health, there are numerous studies showing human health impacts from repeated and high level POP exposure, as well as studies that show POPs accumulate on plastic debris in the marine environment. With this knowledge, there is a need for greater awareness of the risks of POP exposure for those who handle marine debris regularly, especially in contexts of higher exposure such as those working in marine debris concentrated areas. Amongst the scientific community, understanding of the exposure risk might be high, but others who handle marine debris, for instance citizens groups in the global south, are not necessarily aware of this exposure pathway. Moreover, global consumers who are marketed ‘ocean plastics’ upcycled products are also not aware of potential POP exposure. Before marine plastics are accepted into the upcycled economy, these risks warrant further examination. This is a perspectives piece that aims to draw awareness to these emergent POP exposure pathways and considerations regarding marine plastic pollution. This article is protected by copyright. All rights reserved.
Persistent organic pollutants (POPs) are organic compounds that are nondegradable by chemical, biological, and photolytic processes. Because of their continuous bioaccumulation in the environment, they impart drastic effects on human health. The hazardous effects of POPs are so impactful that a special “Stockholm Convention on POPs” was organized in 2001 to highlight the emerging problem. As an early measure, the convention banned or restricted the production of some 12 pollutants worldwide. Besides the endocrinological, gastroenterological, and dermatological complications, these POPs also exert their harmful effects on the nervous system. Clinical signs of Parkinson’s disease, Alzheimer’s disease, stroke, epileptic seizures, multiple sclerosis, dementia, and attention deficit hyperactive syndrome are observed in POPs exposed people. Moreover, in vitro and in vivo studies reveal that organochloride and organophosphate both can cross the blood–brain barrier and damage the dopaminergic, cholinergic, and serotonergic neurons. Additionally, these pollutants can increase or decrease the levels of neurotransmitters and exert oxidative damage to neuronal cells. Certain POPs can activate neuroinflammatory pathways by disrupting expressional levels of proinflammatory and anti-inflammatory cytokines. Presence of a few selective studies with limitations and lack of conclusive outcomes, the exclusive epidemiological studies focusing on the effect of POPs on neurological disorders are lacking in modern-day literature. There is no antidote available in the treatment of organochloride exposure as yet, however for organophosphate exposure, pralidoxime is used. On chronic exposure of POPs, symptomatic treatment is recommended. Such endeavors should be encouraged that highlight the ways of controlling the exposure of pollutants.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxic chemicals which include more than 100 chemicals, mainly produced as a result of improper combustion of organic substances like wood, coal, petrol and oil. These pollutants are released into the environment due to various activities including open air burning, natural losses, leakage of various chemicals, accidental fire and many more. The most common sources of PAHs production are house hold heating systems, plants using coal for gasification and liquefaction, various industries and factories manufacturing different livelihood products, petroleum refineries and automobile exhaust. PAHs metabolites (especially 1-OHP) in urine, and PAH–DNA adducts with DNA, RNA and proteins in WBCs and other tissues, which are part of PAH toxic mechanisms, are used to measure PAH exposure in humans. Despite of different biological barriers such as placenta and blood–brain barrier, brain still has unique susceptibility to environmental risk factors during its developmental period compared with the mature nervous system. Benzo(a)pyrene is one of the most toxic PAHs known which is often used as an indicator of PAH exposure in various epidemiological studies. PAHs combat and interfere with the functions of cellular membrane and its enzyme systems to cause cytotoxicity. Chronic exposure to even low concentration of these chemicals cause ever-lasting damages including infertility, cancer and neurotoxicity to humans as well as wild life. Epigenetic effects, oxidative stress and endocrine disruptions are some of the mechanisms investigated for PAHs neurotoxicity. As brain is the most vulnerable organ to oxidative damage due to low oxygen level which may cause alteration in gene expression, impairment in cellular signaling, membrane integrity disruption, altered neurotransmission and ultimately neuronal cell death. The oxidative stress (due to ROS) produced in the CNS causes reduction in the antioxidant enzymes activities which are crucial for the behavioral effects induced by PAHs especially B(a)P. Adsorption, volatilization, photolysis and chemical degradation are some of the important processes in the removal of PAHs from both the atmosphere and environment. Among these, microbial degradation is considered to be the major PAHs degradation process.
A pollutant with the newly established toxic mode is categorized as an emerging environmental contaminant; many point and non-point sources introduce these contaminants in the environment. Volatile organic compounds (VOCs) are the compounds having a low boiling point, variable lipophilicity and volatility, and are being produced from anthropogenic activities and natural sources. With BTEX (Benzene, toluene, ethylbenzene, and xylene) compounds being most abundant (up to 60%), VOCs are used as a reference for the evaluation of VOC exposure and levels in the environment. VOCs may cause behavioral, neurological, dermatological, and respiratory symptoms in humans as evident from experimental and epidemiological data. Humans are exposed to VOCs through skin, GIT, and lungs. Due to the high lipophilicity of VOCs, they can cross biological membranes and the blood–brain barrier (BBB) and thus resulting in numerous neuropsychiatric disorders, comprising of diminished impulsive control, changes in the motor and cognitive functions, hallucinations, headache, dizziness, and dementia. The mechanism of neurotoxicity of single VOC has not been elucidated completely because VOCs are always present as a mixture, but the possible reason may be the oxidative stress and changes in the neurotransmitters and ion channels functions. Several epidemiological and experimental studies (in vivo and in vitro) have been conducted for assessment of neurotoxic mechanism, risk of acute and chronic exposure, and neurobehavioral changes. BTEX compounds are the most toxic environmental pollutants and cause several neuropsychiatric changes including dementia, headache, nausea, malaise, impairment in learning, and memory; toluene is also associated with leukoencephalopathy, fetal solvent syndrome, and sick building syndrome and targets white matter of the brain. Other VOCs having a higher potential of neurotoxicity include solvents containing chlorine, such as trichloroethylene (TCE), perchloroethylene (PERC) and dichloromethylene, formaldehyde, n-hexane and acetone. VOCs’ occupational exposure level in workers is monitored through the measurement of biomarkers; a recent technique for assessment of environmental agents’ exposure is the measurement of micro-RNAs in plasma/serum. Health risks from VOCs are inevitable due to their ubiquitous nature, and measures should be adopted especially in workplaces, urban and industrial areas to keep the level of toxic VOCs below the operational exposure limit (OELs).
This work focuses on the behavior study of new formulations based on poly vinyl chloride (PVC) and epoxidized sunflower oil (ESO). For that purpose semi-rigid and plasticized sheets were realized. Three plasticizers were considered: the dioctylphtalate (DOP), the di-isodécylphtalate (DIDP) and the di-isononyladipate (DINA). Tests of lixiviation were carried out in two simulators mediums, the acetic acid solution and distilled water at 50 °C while being based on the phenomenon of variation of mass. A soil burial test was realized in a garden (Tizi Ouzou, Algeria)) for six months. The different samples were analyzed by scanning electron microscopy (SEM). The lixiviation test confirmed that the presence of plasticizers and stabilizers affect the phenomenon of migration. The microscopic analysis of bacterial cells in the soil reveals the presence of the Pseudomonas aeruginosa.
Forchlorfenuron (CPPU) has been used worldwide, to boost size and improve quality of various agricultural products. CPPU and its metabolites are persistent and have been detected frequently in fruits, water, sediments, and organisms in aquatic systems. Although the public became aware of CPPU through the exploding watermelon scandal of 2011 in Zhenjiang, China, little was known of its potential effects on the environment and wildlife. In this study, adverse effects of CPPU on developmental angiogenesis and vasculature, which is vulnerable to insults of persistent toxicants, were studied in vivo in zebrafish embryos (Danio rerio). Exposure to 10 mg CPPU/L impaired survival and hatching, while development was hindered by exposure to 2.5 mg CPPU/L. Developing vascular structure, including common cardinal veins (CCVs), intersegmental vessels (ISVs) and sub-intestinal vessels (SIVs), were significantly restrained by exposure to CPPU, in a dose-dependent manner. Also, CPPU caused disorganization of the cytoskeleton. In human umbilical vein endothelial cells (HUVECs) CPPU inhibited proliferation, migration and formation of tubular-like structures in vitro. Results of western blot analyses revealed that exposure to CPPU increased phosphorylation of FLT-1, but inhibited phosphorylation of FAK and its downstream MAPK pathway in HUVECs. In summary, CPPU elicited developmental toxicity to the developing endothelial system of zebrafish and HUVECs. This was do, at least in part due to inhibition of the FAK/MAPK signaling pathway rather than direct interaction with the VEGF receptor (VEGFR).
Intentional weight loss can increase health risk in the long‐term, despite short‐term benefits, because human adipose tissue is widely contaminated with various lipophilic environmental contaminants, especially persistent organic pollutants (POPs). Recently, chronic exposure to low POPs has emerged as a new risk factor for common metabolic diseases and cardiovascular diseases. The amount of POPs released from adipocytes to the circulation increases during weight loss, thereby increasing POPs exposure of other critical organs. Possible harmful effects due to release of POPs during weight loss are opposite to those usually expected from losing weight. It is speculated that this tradeoff can explain recent puzzling findings on intensive weight loss. The presence of POPs in adipose tissue adds a challenge to weight management and an optimal strategy of weight management needs to consider both fat mass and dynamics of POPs. Release of persistent organic pollutants (POPs) and other lipophilic chemicals from adipose tissue to circulation during weight loss can tradeoff short‐term benefits of reduction of fat mass. New approaches considering both fat mass and POPs should be considered during weight loss intervention.
Background
Except for known cardiovascular risk factors, long-term exposure to environmental endocrine disruptors (EEDs) – a class of exogenous chemicals, or a mixture of chemicals, that can interfere with any aspect of hormone action – has been shown to increase the risk of cardiovascular diseases (CVDs), which are still controversial.
Objective
To conduct a comprehensive systematic review and meta-analysis to estimate the association between EEDs, including nonylphenol (NP), bisphenol A (BPA), polychlorinated biphenyl (PCB), organo-chlorine pesticide (OCP) and phthalate (PAE) exposure and CVD risk.
Methods
The heterogeneity between different studies was qualitatively and quantitatively evaluated using Q test and I² statistical magnitude, respectively. Subgroup analysis was performed using chemical homologs – a previously unused grouping method – to extract data and perform meta-analysis to assess their exposure to CVD.
Results
Twenty-nine literatures were enrolled with a total sample size of 88891. The results indicated that exposure to PCB138 and PCB153 were the risk factors for CVD morbidity (odds ratio (OR) = 1.35, 95% confidence interval (CI): 1.10–1.66; OR = 1.35, 95% CI: 1.13–1.62). Exposure to organo-chlorine pesticide (OCP) (OR = 1.12, 95% CI: 1.00–1.24), as well as with phthalate (PAE) (OR = 1.11, 95% CI: 1.06–1.17) and BPA (OR = 1.19, 95% CI: 1.03–1.37).were positively associated with CVD risk, respectively. BPA exposure concentration had no correlation with total cholesterol (TC), or low-density lipoprotein (LDL), but exhibited a correlation with gender, waist circumference (WC), high-density lipoprotein (HDL), age, and body mass index (BMI) (standardized mean difference (SMD) = 1.51; 95%; CI =(1.01–2.25) = 0.16; 95% CI = 0.08–0.23; SMD = −0.19; 95% CI: 0.27–0.12; SMD = −0.78; 95% CI: 1.42–0.14; SMD = 0.08; 95% CI: 0.00–0.16).
Conclusions
EED exposure is a risk factor for CVD. Long-term exposure to EEDs can influence cardiovascular health in humans. A possible synergistic effect may exist between the homologs. The mechanism of which needs to be further explored and demonstrated by additional prospective cohort studies, results of in vitro and in vivo analyses, as well as indices affecting CVD.
In the general population, chronic exposure to low-dose persistent organic pollutants (POPs), particularly organochlorine pesticides (OCPs), has been recently linked to many chronic diseases. Widespread contamination of the food chain and human adipose tissue has made avoiding exposure to these chemicals impossible; thus, alternative strategies for decreasing the chemical burden must be investigated. Recently, macronutrient intake was found to significantly modify the toxicokinetics of POPs in animal experimental studies. Thus, we evaluated whether macronutrient intake was related to serum concentrations of OCPs in healthy adults without cardio-metabolic diseases. Subjects included 1,764 adults, aged 20 years or above, who participated in the National Health and Nutrition Examination Survey 1999-2004. Macronutrient intake was assessed based on a 24-h dietary recall interview. Six individual OCPs commonly detected among the general population were evaluated as markers of OCPs and other coexisting lipophilic chemicals stored in adipose tissue and released into circulation. High fat intake was associated with lower concentrations of OCPs, while high carbohydrate intake showed the opposite result. When three types of fats were individually evaluated, both saturated fatty acids and monounsaturated fatty acids, but not polyunsaturated fatty acids, were inversely associated with serum concentrations of OCPs. Adjustment for possible confounders did not change the results. When stratified by age, gender, body mass index, and physical activity, these associations were similar in most subgroups. Thus, similar to the findings observed in animal experimental studies, a moderate-fat diet with low carbohydrate intake was related to low serum concentrations of OCPs in humans. Although these findings need to be replicated, changing dietary macronutrient intake can be investigated as a practical strategy for dealing with unavoidable lipophilic chemical mixtures such as OCPs in modern society.
Pollution of pristine environmental resources such as water, air, and soil by various anthropogenic activities is becoming a serious cause of concern, worldwide. Besides many other sources of pollution, plastics have emerged as a rapidly spreading environmental pollutant. Excessive use of plastics in various forms in industrial and/or household applications and their further improper disposal have led to water, soil, and air pollution. This has disturbed the ecological balance of marine, freshwater, and terrestrial ecosystems largely. Throughout the history of mankind predicted that by 2050, the ocean will see more plastic in marine water than aquatic species, which highlights an alarming situation if the plastic pollution has not been controlled. Considering this severity, in this book chapter, authors shed a light on the current burning issue of plastic pollution by addressing various aspects such as sources of plastics, their applications, pathways of entering plastic debris in environment, and their deteriorating impacts on ecology and human health. Moreover, preventative and control measures are recommended to avoid the environmental damage caused by various forms of plastics. Case studies specific to Asia-Pacific and European countries are also discussed to highlight the global issue of plastic pollution. In short, this chapter will give readers an insight into global status of plastic pollution, political resolutions, upcoming research trends, and environmental policies to help maintain environmental sustainability by handling the danger of plastic pollution in a rational manner.
Recent studies revealed controversial results on the association of exposure to phthalates with cardiometabolic risk factors in children and adolescents. Therefore, this systematic review and meta-analysis was conducted in this regard. At first, we searched English-language papers in Scopus, Web of Science, and PubMed databases, with no restriction of time, till the end of the year 2018. We performed a comprehensive literature search for association between phthalate exposure and cardiometabolic risk factors including obesity, hypertension, hyperglycemia, and dyslipidemia. Among 99 published papers found in scientific databases, 17 cohort, 15 cross-sectional, and three case-control studies were included in the meta-analysis. We observed a significant association between the concentrations of phthalates and their metabolites with body mass index (BMI), BMI z-score, waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose in serum. In addition, significant association was observed between prenatal phthalate exposure and birth weight. To the best of our knowledge, this is the first meta-analysis of its kind. It shows positive association between phthalate exposure and some cardiometabolic risk factors in children and adolescents. Therefore, prevention of exposure to phthalates and reduction of their use should be underscored in strategies for primordial prevention of cardiovascular diseases.
Recent studies revealed controversial results on the association of exposure to phthalates with cardiometabolic risk factors in children and adolescents. Therefore, this systematic review and meta-analysis was conducted in this regard.
Environmental factors are an important cause of poor health globally. Hypertension is known to occur due to complex interactions between adverse lifestyles and environmental factors on a background of polygenic inheritance. Although pharmacological interventions have taken a prominent place, environmental factors and interventions have generally received less consideration. The short-term and long term impact of several environmental factors on blood pressure changes such as cold ambient temperature, exposure to loud noise, air pollution, high altitude, certain organic pollutants, and heavy metals have been recently reported. In this chapter, the current evidence on the effect of such environmental risk factors on blood pressure with its pathophysiological mechanisms and clinical relevance have been described in detail. As some of these effects are clinically relevant, clinicians, patients with hypertension or cardiovascular disease and individuals at high risk for cardiovascular disease would need to be aware of these environmental factors. Furthermore, close attention to monitoring blood pressure during such exposures is necessary and in individuals with hypertension, treatment schedules may need adjustment to ensure more optimal blood pressure control.
Some obese individuals have normal metabolic profile, and some normal-weight persons have impaired metabolic status. Our hypothesis was that one of the potential underlying factors for such differences in cardiometabolic profiles might be the exposure to some environmental chemicals. This study aimed to investigate the association of serum bisphenol A (BPA) and phthalate metabolites with cardiometabolic risk factors in children and adolescents independent of their weight status. This case–control study was conducted on a subsample of 320 participants of a national school-based surveillance program in Iran. We measured serum BPA and phthalate metabolites by gas chromatography mass spectrophotometry. We compared them in children and adolescents with and without excess weight and those with and without cardiometabolic risk factors (80 in each group). We categorized the concentrations of chemicals to tertiles and then we applied logistic regression models after adjustment for potential confounding factors. The concentrations of BPA and some metabolites of phthalates were significantly different in the four groups studied. MEHP concentration was associated with higher odds ratio of cardiometabolic risk factors in participants with normal weight (OR, 95% CI 2.82, 1.001–7.91) and those with excess weight (OR, 95% CI 3.15, 1.27–7.83). MBP concentration increased the odds ratio of cardiometabolic risk factors only in normal weight children and adolescents (OR, 95% CI 6.59, 2.33–18.59, P < 0.001). In participants without cardiometabolic risk factor, MMP and MEHHP were significantly associated with increased risk of excess weight (OR, 95% CI 5.90, 1.21–28.75 and 7.82, 1.5–41.8, respectively). This study showed that the association of BPA and phthalate with cardiometabolic risk factors is independent of the weight status. Our findings suggest that the metabolic impairment in some normal weight children and normal metabolic profile of some obese children can be, in part, related to exposure to these environmental chemicals. Graphical abstract Graphical abstract
Cross-sectional studies have described an association between exposure to phthalate esters and cardiovascular risk factors. However, the association with coronary heart disease (CHD) is still unclear. A total of 180 subjects randomly selected from 336 CHD patients, and 360 age- and sex-matched non-CHD controls were included from 2008 to 2011. Urinary metabolites of phthalate esters were measured by liquid chromatography–tandem mass spectrometry. The geometric means of urinary phthalates metabolites were significantly higher for the three Di-(2-ethylhexyl)-phthalate (DEHP) metabolites, mono‐2‐ethylhexyl phthalate (MEHP), mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate, and mono‐(2‐ethyl‐5‐oxohexyl) phthalate among CHD patients in-hospital than those of being discharged. Excluding 89 CHD patients of in-hospital and hospital discharge within 2 days, we found the urinary concentrations of MEHP, mono‐n‐butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP) of 91 CHD patients discharged ≥ 3 days were higher than those of controls. Among 451 participants, those with higher tertile levels of urinary MEHP, MnBP, and MiBP showed an increased risk for CHD compared to those with lowest tertile levels; the corresponding odds ratios (95% CI) were 2.77 (1.22–6.28), 2.90 (1.32–6.4), and 3.19 (1.41–7.21), respectively, after adjustment for confounders. Higher levels of hs-CRP, fibrinogen, and D-dimer were linked with increased levels of all DEHP metabolites in CHD patients. In conclusion, exposure to DEHP and dibutyl phthalates was positively associated with CHD and this relationship may be probably mediated via atherothrombosis.
Aims/hypothesis We recently reported associations of some persistent organic pollutants (POPs) with both prevalence of type 2 diabetes and
insulin resistance in a US population with background exposure to POPs. Restricted to non-diabetic participants, we now investigate
the relationship between POPs and the metabolic syndrome, a prediabetic state.
Materials and methods Cross-sectional associations were investigated in 721 non-diabetic participants aged ≥20 years. Nineteen POPs in five subclasses
were selected because they were detectable in ≥60% of participants.
Results Among five POPs subclasses, organochlorine (OC) pesticides were most strongly and consistently associated with metabolic syndrome:
adjusted odds ratios (ORs) of 1.0, 1.5, 2.3 and 5.3 across OC pesticide quartiles (p for trend
This report summarizes results from the Air Force Health Study (AFHS) 2002 follow-up physical examination. The AFHS was undertaken to determine whether adverse health effects attributable to exposure to herbicides existed in veterans of Operation Ranch Hand. The men assigned to Operation Ranch Hand flew aerial herbicide spray missions in Vietnam from 1962 to 1971. A comparison cohort comprised Air Force veterans who served in Southeast Asia during the same time period and who were not involved with spraying herbicides. A total of 1,951 veterans participated in the 2002 physical examination 777 Ranch Hands & 1,174 Comparisons. Statistical analyses assessed differences between Ranch Hands & Comparisons & associations between health- related endpoints & extrapolated initial dioxin, dioxin category, and dioxin measured in 1987. The study has insufficient statistical power to assess increases in the risk of rare diseases. Consistent with past AFHS reports, current results indicate a significant & clinically meaningful adverse relation between type 2 diabetes & exposure to dioxin.
Childhood and adolescent rates of obesity and overweight are continuing to increase in much of the world. Risk factors such as diet composition, excess caloric intake, decreased exercise, genetics, and the built environment are active areas of etiologic research. The obesogen hypothesis, which postulates that prenatal and perinatal chemical exposure can contribute to risk of childhood and adolescent obesity, remains relatively underexamined. This review surveys numerous classes of chemicals for which this hypothesis has been explored. We focus on human data where they exist and also discuss the findings of rodent and cell culture studies. Organochlorine chemicals as well as several classes of chemicals that are peroxisome proliferator-activated receptor agonists are identified as possible risk factors for obesity. Recommendations for future epidemiologic and experimental research on the chemical origins of obesity are also given. Mt Sinai J Med 78:22–48, 2011. © 2011 Mount Sinai School of Medicine
Increased circulating levels of persistent organic pollutants (POPs) have been associated with myocardial infarction. Because myocardial infarction is an atherosclerotic disease, we investigated, in a cross-sectional study, whether POP levels are related to atherosclerosis.
In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1,016 participants 70 years of age), the prevalence of carotid artery plaques was determined by ultrasound. The number of carotid arteries with plaques (0, 1, or 2) was recorded. Also, the intima-media thickness (IMT) and gray scale median of the intima-media complex (IM-GSM) were measured. Twenty-three POPs, comprising 16 polychlorinated biphenyls (PCBs), 5 pesticides, 1 dioxin, and 1 brominated compound (brominated diphenyl ether congener BDE-47), were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry.
Seven of the POPs (PCB congeners 153, 156, 157, 170, 180, 206, and 209) were significantly associated with the number of carotid arteries with plaques even after adjusting for multiple risk factors (sex, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol, serum triglycerides, smoking, antihypertensive treatment, and statin use; p = 0.002-0.0001). Highly chlorinated PCBs (congeners 194, 206, and 209) were associated with an echolucent IM-GSM (p < 0.0001 after adjustment), whereas associations between POPs and IMT were modest.
Circulating levels of PCBs were associated with atherosclerotic plaques and echogenicity of the intima-media complex independent of cardiovascular risk factors, including lipids. This suggests that POPs may be a risk factor for myocardial infarction, but associations need to be confirmed in prospective studies.
To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.
Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.
194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.
Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.
CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).
Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
Although diet and activity are key factors in the obesity epidemic, laboratory studies suggest that endocrine disrupting chemicals may also affect obesity.
We analyzed associations between six phthalate metabolites measured in urine and body mass index (BMI) and waist circumference (WC) in National Health and Nutrition Examination Survey (NHANES) participants aged 6-80. We included 4369 participants from NHANES 1999-2002, with data on mono-ethyl (MEP), mono-2-ethylhexyl (MEHP), mono-n-butyl (MBP), and mono-benzyl (MBzP) phthalate; 2286 also had data on mono-2-ethyl-5-hydroxyhexyl (MEHHP) and mono-2-ethyl-5-oxohexyl (MEOHP) phthalate (2001-2002). Using multiple regression, we computed mean BMI and WC within phthalate quartiles in eight age/gender specific models.
The most consistent associations were in males aged 20-59; BMI and WC increased across quartiles of MBzP (adjusted mean BMI = 26.7, 27.2, 28.4, 29.0, p-trend = 0.0002), and positive associations were also found for MEOHP, MEHHP, MEP, and MBP. In females, BMI and WC increased with MEP quartile in adolescent girls (adjusted mean BMI = 22.9, 23.8, 24.1, 24.7, p-trend = 0.03), and a similar but less strong pattern was seen in 20-59 year olds. In contrast, MEHP was inversely related to BMI in adolescent girls (adjusted mean BMI = 25.4, 23.8, 23.4, 22.9, p-trend = 0.02) and females aged 20-59 (adjusted mean BMI = 29.9, 29.9, 27.9, 27.6, p-trend = 0.02). There were no important associations among children, but several inverse associations among 60-80 year olds.
This exploratory, cross-sectional analysis revealed a number of interesting associations with different phthalate metabolites and obesity outcomes, including notable differences by gender and age subgroups. Effects of endocrine disruptors, such as phthalates, may depend upon endogenous hormone levels, which vary dramatically by age and gender. Individual phthalates also have different biologic and hormonal effects. Although our study has limitations, both of these factors could explain some of the variation in the observed associations. These preliminary data support the need for prospective studies in populations at risk for obesity.
Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly.
Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).
After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8-42.7), and 7.5 (1.4-38.8) (P(trend) <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that P(trend) = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0-11.7) (P(trend) = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes.
Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population.
Procedures for risk assessment of chemical mixtures, combined and cumulative exposures are under development, but the scientific database needs considerable expansion. In particular, there is a lack of knowledge on how to monitor effects of complex exposures, and there are few reviews on biomonitoring complex exposures. In this review we summarize articles in which biomonitoring techniques have been developed and used. Most examples describe techniques for biomonitoring effects which may detect early changes induced by many chemical stressors and which have the potential to accelerate data gathering. Some emphasis is put on endocrine disrupters acting via epigenetic mechanisms and on carcinogens. Solid evidence shows that these groups of chemicals can interact and even produce synergistic effects. They may act during sensitive time windows and biomonitoring their effects in epidemiological studies is a challenging task.
Although it has been hypothesized that fetal exposure to endocrine-disrupting chemicals may increase obesity risk, empirical data are limited, and it is uncertain how early in life any effects may begin.
We explored whether prenatal exposure to several organochlorine compounds (OCs) is associated with rapid growth in the first 6 months of life and body mass index (BMI) later in infancy.
Data come from the INMA (Infancia y Medio-Ambiente) Child and Environment birth cohort in Spain, which recruited 657 women in early pregnancy. Rapid growth during the first 6 months was defined as a change in weight-for-age z-scores > 0.67, and elevated BMI at 14 months, as a z-score ≥ the 85th percentile. Generalized linear models were used to estimate the risk of rapid growth or elevated BMI associated with 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), hexachlorobenzene, β-hexachlorohexane, and polychlorinated biphenyls in first-trimester maternal serum.
After multivariable adjustment including other OCs, DDE exposure above the first quartile was associated with doubling of the risk of rapid growth among children of normal-weight (BMI < 25 kg/m2), but not overweight, mothers. DDE was also associated with elevated BMI at 14 months (relative risk per unit increase in log DDE = 1.50; 95% confidence interval, 1.11-2.03). Other OCs were not associated with rapid growth or elevated BMI after adjustment.
In this study we found prenatal DDE exposure to be associated with rapid weight gain in the first 6 months and elevated BMI later in infancy, among infants of normal-weight mothers. More research exploring the potential role of chemical exposures in early-onset obesity is needed.
Recent evidence suggests that endocrine disrupting chemicals (EDCs) may cause perturbations in endogenous hormonal regulation that predispose to weight gain. Using data from NHANES (1999-2002), we investigated the association between body mass index (BMI), waist circumference (WC) and selected persistent organic pollutants (POPs) via multiple linear regressions. Consistent interaction was found between gender, ln oxychlordane and ln p,p' DDT. Also, we found an association between WC and ln oxychlordane and ln hpcdd in subjects with detectable levels of POPs, whereas an association between WC and ln p,p' DDT was observed in all subjects. Furthermore, ln Ocdd showed an increase with higher WC and BMI, whereas, ln trans-nonachlor decreased with higher BMI. Hence, BMI and WC are associated with POPs levels, making the chemicals plausible contributors to the obesity epidemic.
Low doses of some persistent organic pollutants (POPs) associate cross-sectionally with type 2 diabetes, whereas associations with high POP exposures are inconsistent.
We investigated whether several POPs prospectively predict type 2 diabetes within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort.
Participants in this nested case-control study were diabetes free in 1987-1988. By 2005-2006, the 90 controls remained free of diabetes, whereas the 90 cases developed diabetes. Using serum collected in 1987-1988, we measured 8 organochlorine pesticides, 22 polychlorinated biphenyl congeners (PCBs), and 1 polybrominated biphenyl (PBB). We compared POP concentrations from CARDIA and the National Health and Nutrition Examination Survey (NHANES) in 2003-2004. We computed odds ratios (ORs) for incident diabetes using logistic regression analysis.
Chlorinated POPs in CARDIA in 1987-1988 were much higher than corresponding NHANES 2003-2004 concentrations. POPs showed nonlinear associations with diabetes risk. The highest risk was observed in the second quartiles of trans-nonachlor, oxychlordane, mirex, highly chlorinated PCBs, and PBB153-a finding that suggests low-dose effects. We concentrated risk by summing these POPs and isolated very low concentrations of multiple POPs in the lowest sextile of the sum. The adjusted OR in the second sextile vs. the lowest sextile was 5.3 overall and 20.1 for body mass index > or = 30 kg/m2.
Several POPs at low doses similar to current exposure levels may increase diabetes risk, possibly through endocrine disruption. Certain POPs may a play a role in the current epidemic of diabetes, which has been attributed to obesity.
The associations of 8 pesticides and pesticide metabolites with total diabetes (diagnosed and undiagnosed) and pre-diabetes (glycohemoglobin 5.7-6.4%) were evaluated using the National Health and Nutrition Examination Survey (NHANES), 1999-2004. Six of the pesticides were found to be associated with total diabetes in separate adjusted logistic regressions. These pesticides and pesticide metabolites were beta-hexachlorocyclohexane, p,p'-DDE, p,p'-DDT, oxychlordane, trans-nonachlor, and heptachlor epoxide. When the number of compounds elevated was tested, 4 or more, of the 6, elevated had an odds ratio of 4.99 (95% CI 1.97-12.61) compared to none elevated. When the 6 compounds were tested together in a single combined adjusted logistic regression only oxychlordane, a metabolite of chlordane, and heptachlor epoxide, a metabolite of heptachlor, were significantly associated with total diabetes. In the combined adjusted logistic regression, oxychlordane >or=14.5ng/g lipid adjusted had an odds ratios of 1.90 (95% CI 1.09-3.32) compared to oxychlordane <14.5ng/g lipid adjusted, and heptachlor epoxide >or=14.6ng/g lipid adjusted had an odds ratio of 1.70 (95% CI 1.16-2.49) compared to heptachlor epoxide <14.6ng/g lipid adjusted. Heptachlor epoxide and p,p'-DDT were significantly associated with pre-diabetes in separate adjusted logistic regressions. When these 2 compounds were tested together only heptachlor epoxide remained significantly associated with pre-diabetes. The evidence supporting the relationship between pesticides and pesticide metabolites, with diabetes, was strongest for heptachlor epoxide and oxychlordane, intermediate for p,p'-DDT, and least for beta-hexachlorocyclohexane, p,p'-DDE, and trans-nonachlor. Mirex and dieldrin were not associated with total diabetes or pre-diabetes.
This study was performed to investigate if organochlorine pesticides (OCPs) were associated with metabolic syndrome and insulin resistance among non-diabetes.
Among subjects who participated in a community-based health survey, 50 non-diabetic subjects with metabolic syndrome and 50 normal controls were selected. Insulin resistance was measured by the homeostasis model assessment (HOMA-IR). Eight OCPs were selected.
After adjusting for confounders except for body mass index (BMI), beta-hexachlorocyclohexane (beta-HCH) and heptachlor epoxide were positively associated with metabolic syndrome. Odds ratios across tertiles of beta-HCH and heptachlor epoxide were 1.0, 3.2 and 4.4, and 1.0, 4.0 and 6.0, respectively (p for trend = 0.01 and <0.01). After additional adjustment for body mass index (BMI), heptachlor epoxide still showed an increasing trend with adjusted odds ratios of 1.0, 4.1, and 4.6 (p for trend = 0.10). When the five components of metabolic syndrome (with the definition of high fasting glucose (> or =100 mg/dL)) were separately analyzed, all components were positively, but not significantly, associated with heptachlor epoxide. As the serum concentration of heptachlor epoxide increased, HOMA-IR increased significantly in subjects with metabolic syndrome even after adjusting for BMI (p value <0.05 and <0.01).
Despite the small sample size, this study suggests that the background exposure to some OCPs may be associated with metabolic syndrome.
A heavily polluted area of Eastern Slovakia was targeted by the PCBRISK cross-sectional survey to search for possible links between environmental pollution and both prediabetes and diabetes.
Associations of serum levels of five persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs), 2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), 2,2'-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p'-DDT), hexachlorobenzene (HCB) and beta-hexachlorocyclohexane (beta-HCH), with prediabetes and diabetes were investigated in 2,047 adults. Diabetes and prediabetes were diagnosed by fasting plasma glucose in all participants and by OGTT in 1,220 compliant participants.
Our population was stratified in terms of individual POPs quintiles and associations between environmental pollution, prediabetes and diabetes were investigated. Prevalence of prediabetes and diabetes increased in a dose-dependent manner, with individuals in upper quintiles of individual POPs showing striking increases in prevalence of prediabetes as shown by OR and 95% CI for PCBs (2.74; 1.92-3.90), DDE (1.86; 1.17-2.95), DDT (2.48; 1.77-3.48), HCB (1.86; 1.7-2.95) and beta-HCH (1.97; 1.28-3.04). Interestingly, unlike PCBs, DDT and DDE, increased levels of HCB and beta-HCH seemed not to be associated with increased prevalence of diabetes. Nevertheless, individuals in the 5th quintile of the variable expressing the cumulative effect of all five POPs (sum of orders) had a more than tripled prevalence of prediabetes and more than six times higher prevalence of diabetes when compared with the 1st referent quintile.
Increasing serum concentrations of individual POPs considerably increased prevalence of prediabetes and diabetes in a dose-dependent manner. Interaction of industrial and agricultural pollutants in increasing prevalence of prediabetes or diabetes is likely.
Bisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years.
A cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.
Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.
The incidence of the insulin resistance syndrome has increased at an alarming rate worldwide, creating a serious challenge to public health care in the 21st century. Recently, epidemiological studies have associated the prevalence of type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking.
We investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders.
Sprague-Dawley rats were exposed for 28 days to lipophilic POPs through the consumption of a high-fat diet containing either refined or crude fish oil obtained from farmed Atlantic salmon. In addition, differentiated adipocytes were exposed to several POP mixtures that mimicked the relative abundance of organic pollutants present in crude salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, and gene expression and we performed microarray analysis.
Adult male rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity, and hepatosteatosis. The contribution of POPs to insulin resistance was confirmed in cultured adipocytes where POPs, especially organochlorine pesticides, led to robust inhibition of insulin action. Moreover, POPs induced down-regulation of insulin-induced gene-1 (Insig-1) and Lpin1, two master regulators of lipid homeostasis.
Our findings provide evidence that exposure to POPs commonly present in food chains leads to insulin resistance and associated metabolic disorders.
Global DNA methylation levels have been reported to be inversely associated with blood levels of persistent organic pollutants (POPs), xenobiotics that accumulate in adipose tissue. Whether these associations extend to a population with much lower concentrations of POPs is not known.
This study was performed to examine whether low-dose exposure to POPs was associated with global DNA hypomethylation in Koreans.
The amount of global DNA hypomethylation was estimated by the percent 5-methyl-cytosine (%5-mC) in Alu and LINE-1 assays in 86 apparently healthy Koreans. Among various POPs, organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenylethers (PBDEs) were measured.
Most OC pesticides were inversely and significantly associated with %5-mC in the Alu assay, with correlation coefficients in the range 0.2 to 0.3 after adjusting for age, sex, body mass index, smoking, and alcohol. The strongest OC pesticide associations with %5-mC in the Alu assay were observed with oxychlordane, trans-nonachlor, and p,p -dichlorodiphenyldichloroethylene. The correlation coefficient of age with %5-mC in the Alu assay was 0.24, similar to correlations of OC pesticides with %5-mC in the Alu assay. Most PCBs and PBDEs showed nonsignificant inverse trends with %5-mC in the Alu assay, but for some PCBs the U-shaped association was significant. On the other hand, POPs were not associated with %5-mC in the LINE-1 assay.
We found that low-dose exposure to POPs, in particular OC pesticides, was associated with global DNA hypomethylation in apparently healthy Koreans.
The aim of this study, performed in 2008, was to evaluate the consequences of severe occupational intoxication with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) that occurred during production of the herbicide trichlorophenoxyacetic acid in the period 1965-1968.
Examination of 11 men, mean age 64.4+/-1.5 years, included: internal and neurological examination, eye fundus examination, TCDD in plasma, thyroid-stimulating hormone (TSH), testosterone and serum lipids, ultrasonography of the carotid artery, nerve conduction study (NCS), electroencephalography (EEG), visual evoked potential (VEP), Lanthony test of acquired visual impairment, single photon emission computer tomography (SPECT) of the brain, neuropsychological examination and carbohydrate-deficient transferrin (CDT), a marker of chronic ethanol intake.
Mean TCDD level in 2008 was still 274.0+/-181.2 pg/g blood lipids (reference level is 2-3 pg/g). All (100%) patients had residues of chloracne/chloracne consequences, atherosclerotic changes on the eye fundus and plaques in the carotid arteries. Progression of intima-media thickness (IMT) from a mean of 0.84+/-0.14 mm in 2003 to 1.09+/-0.18 mm in 2008 was observed. Ninety-one per cents of patients had impairment in SPECT of the brain; and 55% of patients had hyperfixation of the perfusion indicator as a measure of increased neuronal activity. Additionally, 91 % of patients were treated for hyperlipidaemia, 73 % for hypertension, 55 % for diabetes type 2, 45 % for ischemic heart disease, and 36 % for psychological disorders. The Lanthony test demonstrated acquired dyschromatopsia in 80 % of patients. Mean colour confusion index (CCI) was 1.438, which indicates impairment since 2003, when the index was 1.302. CDT was in the normal range and did not correlate with CCI. Neuropsychological status appeared stabilized in all 8 patients examined, with impairment in one or more parameter (memory, attention, verbal fluency, psychomotor speed, motorics) in comparison to the norm.
Forty years after intoxication, the blood level of TCDD is still 100 times higher than in the general population. Other PCDD/Fs were not elevated. A high percentage of subjects suffer from neurological and vascular disorders. No association of alcohol consumption with neurological impairment was seen, and the highly significant correlation between CCI and TCDD blood concentration suggests that acquired colour impairment was associated with TCDD but not with alcohol consumption. IMT significantly increased during past 5 years. The patients obviously need complex treatment, including intense hypolipidaemic and antidepressant therapy.
Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes.
A case-control study was performed within a well-defined cohort of women, age 50-59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p'-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p'-DDE).
The results from the present case-control study, including a follow-up design, confirms that p,p'-DDE exposure can be a risk factor for type 2 diabetes.
Studies have demonstrated ubiquitous human exposure to persistent organic pollutants (POPs) such as p,p'-diphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs). Although there is considerable evidence that POP exposures are associated with prevalent diabetes, these studies do not establish causality because the cross-sectional study design does not allow for assessment of temporality of the exposure-disease association. Prospective studies, however, have been lacking.
This study was designed to determine whether POP body burdens are related to incidence of diabetes in a cohort of Great Lakes sport fish consumers.
The cohort was established in the early 1990s and followed through 2005. We tested serum for DDE and PCB congeners and assessed diabetes diagnosis, demographics, and fish consumption. Associations of diabetes with exposures were examined prospectively in participants without diabetes in 1994-1995, followed through 2005. Annual percent changes in DDE and PCB-132/153 from 1994 to 2005 were examined by diabetes status.
DDE exposure was associated with incident diabetes. Incident diabetes was not associated with mono-ortho PCB-118, total PCBs, or years of sport fish consumption. Annual percent change in DDE and PCB-132/153 did not differ significantly by diabetes status.
This study demonstrates an association between DDE exposure and incident diabetes. The findings of an association of DDE with incident diabetes and the lack of effect of diabetes on annual percent change in POPs do not support the hypothesis that associations of POPs with diabetes are attributable to reverse causality. Additional studies should address the biological pathways by which DDE could affect glucose homeostasis.
Environmental exposure to some persistent organic pollutants has been reported to be associated with a metabolic syndrome in the U.S. population.
We evaluated the associations of body burden levels of dioxins and related compounds with the prevalence of metabolic syndrome among the general population in Japan.
We conducted a cross-sectional study with 1,374 participants not occupationally exposed to these pollutants, living throughout Japan during 2002-2006. In fasting blood samples, we measured biochemical factors and determined lipid-adjusted concentrations of 10 polychlorinated dibenzo-p-dioxins (PCDDs), 7 polychlorinated dibenzofurans (PCDFs), and 12 dioxin-like poly-chlorinated biphenyls (DL-PCBs) all of which have toxic equivalency factors. We also performed a questionnaire survey.
The toxic equivalents (TEQs) of PCDDs, PCDFs, and DL-PCBs and total TEQs had significant adjusted associations with metabolic syndrome, whether or not we excluded diabetic subjects. By analyzing each component of metabolic syndrome separately, the DL-PCB TEQs and total TEQs were associated with all components, and the odds ratios (ORs) in the highest quartile of DL-PCB TEQs in four of the five components were higher than those for PCDDs or PCDFs. We also found congener-specific associations with metabolic syndrome; in particular, the highest quartiles of PCB-126 and PCB-105 had adjusted ORs of 9.1 and 7.3, respectively.
These results suggest that body burden levels of dioxins and related compounds, particularly those of DL-PCBs, are associated with metabolic syndrome. Of the components, high blood pressure, elevated triglycerides, and glucose intolerance were most closely associated with these pollutants.
There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n = 48) were treated for 5 months with low concentrations (30 or 300 microg kg(-1) day(-1)) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.
We investigated the association between body mass index (BMI) standard deviation score (SDS) and prenatal exposure to hexachlorobenzene, dichlorodiphenyldichloroethylene (DDE), dioxin-like compounds, and polychlorinated biphenyls (PCBs).
In this prospective birth cohort study, we assessed a random sample of mother-infant pairs (n = 138) living in Flanders, Belgium, with follow-up until the children were 3 years of age. We measured body mass index as standard deviation scores (BMI SDS) of children 1-3 years of age as well as pollutants measured in cord blood.
DDE correlated with BMI SDS, with effect modification by maternal smoking and the child's age. At 1 year, children of smoking mothers had higher BMI SDS than did children of nonsmoking mothers. At 3 years, this difference was reduced because of the faster rate of decline in BMI SDS in the former group. This relationship held except for children with high levels of DDE. DDE had a small effect on BMI SDS at 3 years of age in children of nonsmoking mothers (difference in BMI SDS for DDE concentrations between the 90th and 10th percentiles = 0.13). On the other hand, smoking enhanced the relation between DDE and BMI SDS at 3 years (difference in BMI SDS for DDE concentrations between the 90th and 10th percentiles = 0.76). Increasing concentrations of PCBs were associated with higher BMI SDS values at all ages (parameter estimate = 0.003 +/- 0.001; p = 0.03).
In this study we demonstrated that intrauterine exposure to DDE and PCBs is associated with BMI during early childhood. Future studies are warranted to confirm our findings and to assess possible mechanisms by which these pollutants could alter energy metabolism.
To investigate the effect of prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyl-dichloroethylene (DDE) on weight, height and body mass index (BMI) in adult female offspring of the Michigan fisheater cohort examined between 1973 and 1991.
259 mothers from the Michigan fisheater cohort were studied. Prenatal exposure to PCBs and DDE was estimated by extrapolating maternal measurements to the time that the women gave birth. 213 daughters aged 20-50 years in 2000 were identified and 83% of them participated in at least one of two repeated investigations in 2001/02 (n = 151) and 2006/07 (n = 129). To assess the effect of prenatal PCB and DDE exposure on anthropometric measurements, generalised estimating equations nested for repeated measurements (2001/02 and 2006/07) and for sharing the same mother were used. We controlled for maternal height and BMI and for daughters' age, birth weight, having been breastfed and number of pregnancies.
Maternal height and BMI were significant predictors of the daughters' height, weight and BMI. Low birth weight (<2500 g) was significantly associated with reduced adult offspring weight and BMI. The weight and BMI of adult offspring were statistically significantly associated with the extrapolated prenatal DDE levels of their mothers. Controlling for confounders and compared to maternal DDE levels of <1.503 microg/l, offspring BMI was increased by 1.65 when prenatal DDE levels were 1.503-2.9 microg/l and by 2.88 if levels were >2.9 microg/l. Prenatal PCB levels showed no effect.
Prenatal exposure to the oestrogenic endocrine-disrupting chemical DDE may contribute to the obesity epidemic in women.
The purpose of this study was to investigate the association between organochlorine (OC) pesticides and the prevalence of peripheral arterial disease (PAD).
This study included 2032 participants from the National Health and Nutrition Examination Survey (1999-2004), in which the ankle brachial index (ABI) and serum levels of OC pesticides (p,p'-DDE, trans-nonachlor, oxychlordane, dieldrin, and β-HCH) were measured simultaneously. A diagnosis of PAD was determined on the basis of an ABI<0.9. The obesity status was categorized as obese group (BMI ≥ 25 kg/m(2)) or non-obese group (BMI<25 kg/m(2)). Compared with subjects without PAD, those with PAD had significantly higher lipid-standardized and wet-weight concentrations of OC pesticides. Obese subjects with PAD had significantly increased mean lipid-standardization value of p,p'-DDE (OR=1.47; 95% CI, 1.08-1.99), trans-nonachlor (OR=1.68; 95% CI, 1.10-2.56), oxychlordane (OR=1.82; 95% CI, 1.09-3.03), dieldrin (OR=2.36; 95% CI, 1.69-3.31), and sums of all five pesticides (OR=1.19; 95% CI, 1.07-1.33). For non-obese group, increases in the levels of OC pesticides and their sums did not account for increased risk ratio of PAD.
OC pesticides are a potent risk factor for PAD. Additionally, obesity may modulate the association between OC pesticides and the development of PAD.
THE SECOND report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II, or ATP II) presents the National Cholesterol Education Program's updated recommendations for cholesterol management. It is similar to the first in general outline, and the fundamental approach to treatment of high blood cholesterol is comparable. This report continues to identify low-density lipoproteins (LDL) as the primary target of cholesterol-lowering therapy. As in the first report, the second report emphasizes the role of the clinical approach in primary prevention of coronary heart disease (CHD). Dietary therapy remains the first line of treatment of high blood cholesterol, and drug therapy is reserved for patients who are considered to be at high risk for CHD. However, the second report contains new features that distinguish it from the first. These include the following:
Increased emphasis on
See also pp 3002 and 3009.
LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
Objective:
To determine risk factors for elevated blood pressure and hypertension in residents of Anniston, Alabama who live near a plant that manufactured polychlorinated biphenyls (PCBs).
Methods:
A total of 758 Anniston residents had multiple measurements of blood pressure, provided information on demographic factors, medications, smoking, and exercise, and provided blood samples for determination of PCBs and total serum lipid.
Results:
Rates of hypertension increased significantly (P < 0.05) with age and concentration of serum PCBs and were higher in African-Americans (n = 351) than in whites (n = 407). Hypertension also increased with BMI, but was not related to total serum lipid, sex, smoking, or exercise. Among 394 persons not on antihypertensive medication, linear regression analysis demonstrated a significant positive relation between serum PCB level and both systolic and diastolic blood pressure. After adjustment for potentially confounding variables, logistic regression gave odds ratios for the highest to lowest tertiles of total serum PCBs that exceeded 3.5 for both systolic and diastolic hypertension. When analyzed by quintiles of PCBs, the highest odds ratio was in the third quintile, suggesting a low dose effect.
Conclusion:
In individuals not on antihypertensive medication, serum PCB levels were significantly associated with prevalence of hypertension. Significant positive associations were also observed between PCB concentrations and systolic and diastolic blood pressure even in normotensive ranges. The strength of the relationships between PCB exposure and both hypertension and blood pressure suggests that PCB exposure may be an important contributing factor in regulation of blood pressure.
Recent studies have demonstrated ubiquitous exposure to persistent organic pollutants (POPs) such as p,p′-diphenyldichloroethene (DDE), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Although several studies have noted associations of dioxins, PCBs and DDE with diabetes, the results have not always been consistent, with few examining effects of PBDEs or simultaneous exposures. The purpose of this study was to determine whether POP body burdens are related to diabetes in a cross section of Great Lake sport fish consumers. The cohort, which was established in the early 1990s, was recontacted in 2004–2005. Serum was collected and tested for DDE, PCBs, PBDEs, hemoglobin A1c and lipids, and diabetes diagnosis, demographics and fish consumption were assessed by self report. Associations of diabetes with exposures were examined in cross sectional data from 2004 to 2005. DDE exposure and dioxin-like mono-ortho PCBs were associated with diabetes, but the association of dioxin-like mono-ortho PCBs with diabetes did not remain significant after control for DDE exposure. Neither the sum of PCBs or years of sport fish consumption were associated with prevalent diabetes. There was a non-significant association of PBDEs with diabetes only in those with hypothyroid disease. The current study confirms previous cross sectional associations of DDE exposure with diabetes. Future studies should address biologic pathways by which selective POPs affect glucose homeostasis.
A rapid analytical screening method allowing simultaneous analysis of 23 persistent organic pollutants (POPs) in human plasma was developed. Sample preparation based on solid-phase extraction (SPE) with additional clean-up using small multilayer silica gel columns. SPE was performed using a custom made polystyrene-divinylbenzene sorbent for the extraction of chlorinated and brominated POPs. Special efforts to reduce sample volume and improve speed and efficiency of the analytical procedure were made. Determination of 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin (OCDD) and polybrominated diphenyl ether (BDE #47) in 0.5 mL human plasma was performed by using high resolution gas chromatography coupled to high resolution mass spectrometry (HRGC/HRMS). Recovery of POPs ranged between 46% and 110%, and reproducibility was below 25% relative standard deviation (RSD) for all target compounds, except for trans-nonachlor and OCDD, which were present only at low levels. Limits of detection (LOD) were for the PCBs between 0.8 and 117.7 pg mL(-1) plasma and for the OC pesticides between 5.9 and 89.1 pg mL(-1) plasma. The LOD for OCDD and BDE #47 were 1.4 pg mL(-1) plasma, and 9.2 pg mL(-1) plasma, respectively. The presented method was successfully applied to 1016 human plasma samples from an epidemiological study on cardiovascular disease.
In animal experiments, persistent organic pollutants (POPs) have induced visceral obesity. To address this possibility in humans, we evaluated associations between POPs and abdominal obesity both cross-sectionally and prospectively.
Twenty-one plasma POPs (16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured at baseline in 970 participants aged 70 years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), with prospective analyses in 511 participants re-examined after 5 years. Abdominal obesity was defined by an increased waist circumference.
In the cross-sectional analyses, concentrations of the less chlorinated PCBs, OC pesticides such as p,p'-DDE and dioxin had adjusted odds ratios of 2 to 3 for abdominal obesity. Many relations had inverted U-shapes rather than being linear, particularly in women. In contrast, concentrations of highly chlorinated PCBs were strongly inversely associated with abdominal obesity. In a single model including summary measures of the less chlorinated PCBs, highly chlorinated PCBs, and OC pesticides, both the positive associations and inverse associations strengthened. Similar but somewhat weaker associations were seen between POPs and risk of development of abdominal obesity in the prospective analyses.
Using both a cross-sectional and a prospective design, low-dose exposure to less chlorinated PCBs, p,p'-DDE, and dioxin, were associated with existence or development of abdominal obesity, while highly chlorinated PCBs had an opposite association in an elderly population, despite the previous observation of higher incident diabetes associated with these same PCBs.
The Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures (Mixtures Guidance Manual) is intended to assist environmental health scientists and toxicologists in determining whether exposure to chemical mixtures at hazardous waste sites may affect public health. The Agency for Toxic Substances and Disease Registry (ATSDR) approach is a semi-quantitative screening process. Step-by-step procedures for assessing noncarcinogenic and carcinogenic effects are outlined in flow charts. Exposure data and toxicological information on the mixture of concern are the preferred basis for an assessment. If suitable whole mixture studies are not available, a components-based approach is undertaken. The hazard index (HI) method is used to screen for noncancer health hazards from potential additivity of the components. Cancer risks for the components are summed to screen for health hazards from potential additivity of carcinogenic effects. A weight-of-evidence (WOE) method is used to evaluate the potential impact of interactions on noncancer and cancer health effects.
Persistent organic chemicals, such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), dioxins, and polychlorinated biphenyls, pose investigative challenges because they are found in virtually everyone (there is no unexposed control group). To overcome this problem, outcome data in some studies are sorted by chemical dose level and findings in low-end dose groups are compared to sequential higher dose groups. An example is the C8 Health Project that evaluated serum PFOA/PFOS (C8) and total cholesterol among 46,294 West Virginia residents who lived, worked, or went to school for at least 1 year in a C8 contaminated drinking-water district and were over age 18 in 2005-2006. The risk for high total cholesterol (>240 mg/dL) measured via odds ratios (ORs) in logistic regression models showed sequential OR increases with PFOA quartile, in comparison to the lowest quartile (OR = 1.00), that were each significantly elevated (OR = 1.21, 1.33, and 1.40, respectively), but age, sex, and body mass index were stronger correlates. Importantly, the magnitude of cholesterol increase was small (12 mg/dL from lowest to highest exposure deciles) and comparison to similar statistics for the general U.S. population showed the C8 cohort had lower rates of high cholesterol. This suggests that inadvertent selection bias may have affected the lowest exposure quartile (control group), making tenuous the dose-response relationship between PFOA/PFOS and risk of high cholesterol. This case illustrates the substantial difficulties in assigning toxicological importance to statistical comparisons for common disease states that utilize subgroups with low exposures as an effective control group.
Environmental contaminants have recently been implicated in the pathogenesis of obesity.
To explore relations between persistent organic pollutants (POPs) and fat mass independently of body stature, using a cross-sectional design.
In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), fat mass was determined in 70-year-old subjects (n=890) by dual-energy X-ray absorptiometry (DXA). The plasma levels of 21 POPs (including 16 PCB congeners, 3 OC pesticides, 1 BDE47, and 1 dioxin) were measured by high resolution chromatography coupled with high resolution mass spectrometry (HRGC/HRMS).
Lipid-standardized plasma concentrations of octachlorodibenzo-p-dioxin (OCDD), the PCBs 74, 99, 105 and 118, and the pesticides HCB, TNK, and DDE were all positively related to fat mass (p=0.03-0.0001). Subjects in the fifth quintile for PCB 105 showed a mean fat mass that was 4.8 kg more than subjects in the first quintile. On the other hand, the PCBs 156, 157, 169, 170, 180, 189, 194, 206, and 209 were negatively related to fat mass (p=0.0001). For PCB 194, subjects in the fifth quintile showed a mean fat mass that was 10.8 kg less than subjects in the first quintile. Following adjustment for smoking, physical activity, education level, height, lean mass, and gender, these results remained significant (p=0.01-0.0001) except for the PCBs 74 and 99. For some PCBs, the associations vs. fat mass were more pronounced in women than in men.
Plasma concentrations of some pesticides are positively related to fat mass, while divergent associations are seen for the PCBs. These results implicate a complex role of POPs in obesity.
The aim of this study was to evaluate the associations of environmental exposure to dioxins with diabetes among general inhabitants in Japan. A cross-sectional study was performed on 1374 participants, who were not occupationally exposed to dioxins, aged 15-73 years, living widely in 75 different residential areas of 25 prefectures in Japan through 2002-2006. Seven polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs), which are assigned a toxic equivalency factor, and biochemical factors were determined in fasting blood. A questionnaire survey on life-style including past history of diseases and treatments was also performed. We examined the associations of the accumulated toxic equivalents (TEQs) of PCDDs+PCDFs, dioxin-like PCBs and total dioxins with prevalent diabetes. Simple and partial correlation analyses revealed that HbA1c correlated with the accumulated TEQs of PCDDs+PCDFs, dioxin-like PCBs and total dioxins. In logistic regression analyses, the third and the highest quartiles of dioxin-like PCBs had adjusted odds ratios (ORs) of 3.07 (95% CI 1.16-8.81) and 6.82 (95% CI 2.59-20.1) compared to the reference (first plus second quartiles). On the other hand, the highest but not the third quartiles of PCDDs+PCDFs and total dioxins had significantly higher adjusted ORs compared to the respective references. These associations persisted when the subjects with poor liver or poor renal function were removed from the analysis. This recent representative data from general inhabitants in Japan showed associations of environmental exposure to dioxins, especially dioxin-like PCBs, with diabetes.
Data from several epidemiologic studies suggest that exposure to unusually high amounts of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) increases the risk of diabetes mellitus, and experimental data suggest that the mechanism for this is decreased cellular glucose uptake. To investigate the dose-response relation more closely, we examined the association of serum dioxin level with prevalence of diabetes mellitus and with levels of serum insulin and glucose among 1,197 veterans in the Air Force Health Study who never had contact with dioxin-contaminated herbicides and whose serum dioxin level was within the range of background exposure typically seen in the United States (< or =10 ng/kg lipid). Compared with those whose serum dioxin level was in the first quartile (<2.8 ng/kg lipid), the multivariate-adjusted odds of diabetes among those in the highest quartile (> or =5.2 ng/kg lipid) was 1.71 (95% confidence interval = 1.00-2.91). The association was slightly attenuated after adjustment for serum triglycerides. Whether adjustment for serum triglycerides was appropriate, however, cannot be determined with available data. The association of background-level dioxin exposure with the prevalence of diabetes in these data may well be due to reasons other than causality, although a causal contribution cannot be wholly dismissed.
Bisphenol A (BPA) levels have previously been associated with coronary heart disease (CHD). Since CHD is an atherosclerotic disease, we investigated if circulating levels of BPA and phthalate metabolites are related to atherosclerosis in a cross-sectional study.
In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), the prevalence of overt plaques and echogenectity (grey scale median, GSM) of carotid artery plaques were recorded by ultrasound in both of the carotid arteries. The thickness (IMT) and echogenicity (IM-GSM) of the intima-media complex were also measured. Bisphenol A (BPA) and 10 phthalate metabolites were analyzed in serum by a API 4000 liquid chromatograph/tandem mass spectrometer.
Mono-methyl phthalate (MMP) was related to carotid plaques in an inverted U-shaped manner. This pattern was significant after adjustment for gender, body mass index, blood glucose, blood pressure, HDL and LDL-cholesterol, serum triglycerides, smoking, antihypertensive treatment and statin use (p=0.004). High levels of BPA, mono-isobutyl phthalate (MiBP) and MMP were associated with an echogenic IM-GSM and plaque GSM, while high levels of mono-2-ethylhexyl phthalate (MEHP) were associated with an echolucent IM-GSM and plaque GSM (p<0.0001 after adjustment).
The phthalate metabolite MMP was related to atherosclerotic plaques in an inverted U-shaped manner independently of CV risk factors. Some phthalates and BPA were also related to the echogenicity of the plaques, suggesting a role for plaque-associated chemicals in atherosclerosis.
Exposure to dioxins has been shown to contribute to the development of inflammatory diseases, such as atherosclerosis. Macrophage-mediated inflammation is a critical event in the initiation of atherosclerosis. Previously, we showed that treatment of macrophages with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to aryl hydrocarbon receptor (AhR)-dependent activation of inflammatory mediators and the formation of cholesterol-laden foam cells. However, the mechanisms responsible for the formation of atherosclerotic lesions mediated through AhR have not been identified.
An in vitro macrophage and an apolipoprotein E (ApoE)-/- mouse model were used to determine whether chemokines and their receptors are responsible for the AhR-mediated atherogenesis. Exposure of ApoE-/- mice to TCDD caused a time-dependent progression of atherosclerosis, which was associated with induction of inflammatory genes, including interleukin-8, as well as F4/80 and matrix metalloproteinase-12. A high-fat diet enhanced the TCDD-mediated inflammatory response and aggravated the formation of complex atheromas. Treatment with a CXCR2 inhibitor and an AhR antagonist reduced the TCDD-induced progression of early atherosclerotic lesions in ApoE-/- mice.
The results suggest that CXCR2 mediates the atherogenic activity of environmental pollutants, such as dioxins, and contributes to the development of atherosclerosis through the induction of a vascular inflammatory response by activating the AhR-signaling pathway.
2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) causes abnormalities during heart development. Cardiomyocytes derived from embryonic stem (ES) cells are a robust model for the study of early cardiomyogenesis. Here, we evaluated the effects of TCDD at key stages during the differentiation of mouse ES cells into cardiomyocytes analysing: (i) the transcription of lineage differentiation (Brachyury, Nkx-2.5, Actc-1), cardiac-specific (Alpk3, cTnT, cTnI, cTnC) and detoxification phase I (Cyp1A1, Cyp1A2 and Cyp1B1) and phase II (Nqo1, Gsta1 and Ugt1a6) genes; (ii) the global gene expression; (iii) the ultrastructure of ES-derived cardiomyocytes; (iv) level of ATP production and (v) the immunolocalisation of sarcomeric α-actinin, β-myosin heavy chain and cTnT proteins. We show that TCDD affects the differentiation of ES cells into cardiomyocytes at several levels: (1) induces the expression of phase I genes; (2) down-regulates a group of heart-specific genes, some involved in the oxidative phosphorylation pathway; (3) reduces the efficiency of differentiation; (4) alters the arrangement of mitochondria, that show twisted and disrupted cristae, and of some sarcomeres, with misalignement or disarrangement of the myofibrillar organisation and (5) reduces ATP production. This study provides novel evidences that TCDD impairs cardiomyocyte differentiation. Sarcomeres and mitochondria could be a target for dioxin toxicity, their disruption representing a possible mechanism developing cardiac injury.
High prevalence of thyroid and metabolic disorders has been repeatedly observed in the population living in the area of eastern Slovakia highly polluted by a mixture of PCBs, DDE and HCB since about 50 years ago. Among thyroid disorders, increase of thyroid volume as measured by ultrasound volumetry may be suggested as one of notable findings which appeared possibly related to increased OCs levels and to autoimmunity signs (e.g. positive thyroperoxidase antibodies in blood and/or hypoechogenicity image obtained by ultrasound), while some participation of individual susceptibility and also of immunogenic effect of OCs and iodine in this iodine replete country cannot be excluded. Another notable finding has been the increase of blood FT4 and TT3 positively related to high PCBs level. Such increased FT4 level has been found associated with TSH level in hyperthyroid range in about 2% of examined population from polluted area. High prevalence of thyroid autoimmune disorders strongly supported the assumption on impaired immune system and thus also on presumably increased prevalence of other autoimmune disorders in highly exposed population. In addition, markedly increased prevalence of prediabetes and diabetes significantly related to major OCs (PCBs, DDE and HCB) levels and accompanied by increasing level of cholesterol and triglycerides has been observed. The observations also suggested a role of prenatal exposure to OCs in the development of several adverse health signs (e.g. increased prevalence of thyroid antibodies, impaired fasting glucose level, increased thyroid volume, decreased thymus volume, decreased neurobehavioral performance, increased hearing and dental disorders) in young generation born to highly exposed mothers in polluted area.
National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10-14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension.
Dioxin exposure has been positively associated with human type II diabetes. Because lipophilic dioxins accumulate mainly in adipose tissue, this study aimed to determine if dioxins induce metabolic dysfunction in fat cells. Using 3T3-L1 cells as an in vitro model, we analyzed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model dioxin, on adipogenic differentiation, glucose uptake, and lipolysis. TCDD inhibited adipogenic differentiation, as determined by using oil droplet formation and adipogenic marker gene expression, including PPARgamma (peroxisome proliferator-activated receptor gamma), C/EBPalpha (CCAAT/enhancer-binding protein alpha), and Glut4 (glucose transporter type 4). Effects of TCDD on glucose uptake were evaluated using fully differentiated 3T3-L1 adipocytes, revealing that TCDD significantly attenuated insulin-induced glucose uptake dose dependently. Inhibition of aryl hydrocarbon receptor (AhR) by alpha-naphthoflavone (alpha-NF), an AhR inhibitor, did not prevent the inhibitory effect of TCDD on glucose uptake, suggesting that TCDD attenuates insulin-induced glucose uptake in an AhR-independent manner. Effects of TCDD on lipolysis were determined using glycerol release assay. We found that TCDD had no marked effect on isoproterenol-induced glycerol release in fully differentiated 3T3-L1 adipocytes. These results provide in vitro evidence of TCDD's effects on fat cell metabolism, suggesting dioxin exposure in development of insulin resistance and type II diabetes.
Persistent organic pollutants (POPs) are endocrine-disrupting chemicals associated with the development of the metabolic syndrome and type 2 diabetes. In humans, little is known about their role in the potential origin of obesity. This study aims to assess the associations between serum levels of POPs and the prevalence of obesity in a cohort of obese and lean adult men and women. POP serum samples were investigated cross-sectionally in 98 obese and 47 lean participants, aged ≥18 years. Serum samples were analyzed for the presence of polychlorinated biphenyl (PCB) congeners 153, 138, 180, and 170 and for the organochlorine pesticides, dichloro-diphenyl-dichloroethylene (pp-DDE), and β-hexachlorocyclohexane (βHCH). We established a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissue, and serum levels of PCB 153, 180, 170, and the sumPCBs. For βHCH, we demonstrated a positive correlation with BMI, waist, fat mass percentage, and total and subcutaneous abdominal adipose tissue. PCBs 180, 170, and the sum of PCBs correlated significantly negative with homeostasis model assessment for insulin resistance (HOMA(IR)). βHCH correlated significantly positively with HOMA(IR). A strong correlation was established between all POP serum levels and age. We established a positive relationship between high serum levels of βHCH and BMI and HOMA(IR), whereas serum PCB levels were inversely correlated with BMI and HOMA(IR). Combined, these results suggest that the diabetogenic effect of low-dose exposure to POPs might be more complicated than a simple obesogenic effect.
Low-dose organochlorine (OC) pesticides have recently been associated with type 2 diabetes in several non-Asian general populations. As there is currently epidemic type 2 diabetes in Asia, we investigated the associations between OC pesticides and type 2 diabetes in Koreans. Among subjects who participated in a community-based health survey, we randomly selected 40 diabetic patients and 40 normal controls. Ten OC pesticides (beta-hexachlorocyclohexane, hexachlorobenzene, heptachlor epoxide, p,p'-DDE, p,p'-DDD, p,p'-DDT, o,p'-DDT, oxychlordane, trans-nonachlor, and mirex) detectable in >or=70% of controls were analyzed in relation to diabetes. Most OC pesticides showed strong associations with type 2 diabetes after adjusting for age, sex, BMI, alcohol consumption, and cigarette smoking. Compared with subjects in the lowest tertile of each OC pesticide, adjusted odds ratios (ORs) in the 3rd tertile ranged from 3.1 (95% CI 0.8-12.1) for heptachlor epoxide to 26.0 (95% CI 1.3-517.4) for oxychlordane. In the case of chemicals belonging to the DDT family, adjusted ORs in the 3rd tertile were in the range of 10.6 (95% CI 1.3-84.9) for p,p'-DDT to 12.7 (95% CI 1.9-83.7) for p,p'-DDE. In this exploratory study with small sample, low-dose background exposure to OC pesticides was strongly associated with prevalent type 2 diabetes in Koreans even though absolute concentrations of OC pesticides were no higher than in other populations. Asians may be more susceptible to adverse effects of OC pesticides than other races.
The aryl hydrocarbon receptor (AhR) also known as the dioxin receptor or xenobiotic receptor is a member of the basic helix-loop-helix/period AhR nuclear translocator single minded family. The goal of this study was to determine the endobiotic role of AhR in hepatic steatosis.
Wild-type, constitutively activated AhR transgenic, AhR null and CD36/fatty acid translocase null mice were used to investigate the role of AhR in steatosis and the involvement of CD36 in the steatotic effect of AhR. The promoters of the mouse and human CD36 genes were cloned and their regulation by AhR was analyzed.
Activation of AhR induced spontaneous hepatic steatosis characterized by the accumulation of triglycerides. The steatotic effect of AhR likely is owing to the combined up-regulation of CD36 and fatty acid transport proteins, suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, increase in peripheral fat mobilization, and increased hepatic oxidative stress. Promoter analysis established CD36 as a novel transcriptional target of AhR. Activation of AhR in liver cells induced CD36 gene expression and enhanced fatty acid uptake. The steatotic effect of an AhR agonist was inhibited in CD36-/- mice.
Our study reveals a novel link between AhR-induced steatosis and the expression of CD36. Industrial or military exposures to dioxin and related compounds have been linked to increased prevalence of fatty liver in human beings. Results from this study may help to establish AhR and its target CD36 as novel therapeutic and preventive targets for fatty liver disease.
Epidemiological and laboratory studies suggested that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects glucose homeostasis and increases the incidence of type 2 diabetes mellitus. To evaluate the effects of TCDD on insulin secretion from islets of Langerhans (islets), we designed in vivo, ex vivo and in vitro experiments. For the in vivo experiment, male C57BL/6J and aryl hydrocarbon receptor (AhR)-null mice were injected intraperitoneally with TCDD (10 microg kg(-1) b.w.), fasted for 12 h and administered glucose 24 h post-administration. TCDD exposure significantly decreased the plasma insulin concentration at 60 and 120 min after a glucose challenge in C57BL/6J mice but not in AhR-null mice. In contrast, the plasma glucose concentration was not changed by TCDD exposure in both C57BL/6J and AhR-null mice. For the ex vivo experiment, we isolated islets 24 h after TCDD administration and determined the glucose-stimulated insulin secretion from the islets. The insulin secretion level was found to be significantly decreased by TCDD exposure at 60 min after glucose treatment. For the in vitro experiment, islets harvested from untreated C57BL/6J mice were exposed to 0.1, 1, 10 or 100 nM TCDD for 24 h and analyzed for glucose-stimulated insulin secretion. Insulin secretion from the islets remained unchanged regardless of TCDD dose. In conclusion, TCDD exposure impaired the second phase of glucose-stimulated secretion of insulin from the islets via the AhR signaling pathway.
The endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in wildlife and humans. Many of these chemicals may interact with members of the nuclear receptor superfamily. Peroxisome proliferator-activated receptors (PPARs) are such candidate members, which interact with many different endogenous and exogenous lipophilic compounds. More particularly, the roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named "metabolic disrupters". Phthalates are abundant environmental micro-pollutants in Europe and North America and may belong to this class. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.