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Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice
Abstract
Background: Exposure to arsenic is a major concern in the United States and worldwide, since this metalloid has been associated with a number of ailments, including cardiovascular and metabolic diseases.
... Prenatal arsenic exposure has been related to altered gene expression in diabetes pathways in newborns [12][13][14][15][16]. In rodent models, prenatal arsenic induces diabetes in adult offspring [17][18][19][20][21]. It is also known that maternal nutrition during pregnancy influences programming for adiposity and diabetes This article is part of the Topical Collection on Diabetes Epidemiology risk in adult life. ...
... Five studies (three in mice, two in rats) have evaluated the role of in utero arsenic exposure with diabetes in the offspring (Table 1) [17][18][19][20][21]. Two studies included a pre-mating exposure period and three studies included a post-birth exposure period (one of them splitting the litter to compare in utero only vs. both in utero and post-birth). ...
... In the four studies evaluating the homeostatic model assessment (HOMA), a measurement of insulin resistance, the offspring exposed to arsenic in utero showed elevated HOMA levels compared with unexposed offspring [17][18][19][20]. In utero arsenic exposure also resulted in positive histological scores for non-alcoholic fatty liver disease (NAFLD), which is tightly linked to insulin resistance, in the two studies evaluating this outcome [21]. Overall, these experimental studies support that in utero arsenic exposure influences the early programming of diabetes and related complications later in life. ...
Purpose of Review
In utero influences, including nutrition and environmental chemicals, may induce long-term metabolic changes and increase diabetes risk in adulthood. This review evaluates the experimental and epidemiological evidence on the association of early-life arsenic exposure on diabetes and diabetes-related outcomes, as well as the influence of maternal nutritional status on arsenic-related metabolic effects.
Recent Findings
Five studies in rodents have evaluated the role of in utero arsenic exposure with diabetes in the offspring. In four of the studies, elevated post-natal fasting glucose was observed when comparing in utero arsenic exposure with no exposure. Rodent offspring exposed to arsenic in utero also showed elevated insulin resistance in the 4 studies evaluating it as well as microRNA changes related to glycemic control in 2 studies. Birth cohorts of arsenic-exposed pregnant mothers in New Hampshire, Mexico, and Taiwan have shown that increased prenatal arsenic exposure is related to altered cord blood gene expression, microRNA, and DNA methylation profiles in diabetes-related pathways. Thus far, no epidemiologic studies have evaluated early-life arsenic exposure with diabetes risk. Supplementation trials have shown B vitamins can reduce blood arsenic levels in highly exposed, undernourished populations. Animal evidence supports that adequate B vitamin status can rescue early-life arsenic-induced diabetes risk, although human data is lacking.
Summary
Experimental animal studies and human evidence on the association of in utero arsenic exposure with alterations in gene expression pathways related to diabetes in newborns, support the potential role of early-life arsenic exposure in diabetes development, possibly through increased insulin resistance. Given pervasive arsenic exposure and the challenges to eliminate arsenic from the environment, research is needed to evaluate prevention interventions, including the possibility of low-cost, low-risk nutritional interventions that can modify arsenic-related disease risk.
... These maternal changes can impair placental function and lead to alterations in fetal liver responses that promote a pathological phenotype in offspring (25). In this minireview, we highlight rodent studies examining the link between developmental and gestational exposures of EDCs on NAFLD development/progression (Fig. 1), identify potential mechanisms underlying this link (Table 1) (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), and discuss the translational relevance of such exposures to NAFLD development in humans. ...
... In Swiss Webster mice exposed to 100 parts per billion sodium arsenite from embryonic day 6 until parturition, sodium arsenite induced a fatty liver phenotype, as evidenced by Oil Red O staining, compared with sodium chloride controls (43). This was accompanied by hyperglycemia, as well as higher cholesterol, low-density lipoprotein, and high-density lipoprotein levels. ...
... This was accompanied by hyperglycemia, as well as higher cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Fibrosis was not increased in exposed animals, nor ALT, AST, or alkaline phosphatase, indicating that NAFLD is present without full-blown NASH (43). ...
Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic worldwide, particularly in countries that consume a Western diet, and can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma (HCC). With increasing prevalence of NAFLD in both children and adults, an understanding of the factors that promote NAFLD development and progression is crucial. Environmental agents, including endocrine-disrupting chemicals (EDCs), that have been linked to other diseases may play a role in NAFLD development. Increasing evidence supports a developmental origin of liver disease and early-life exposure to EDCs could represent one risk factor for the development of NAFLD later in life. Rodent studies provide the strongest evidence for this link, but further studies are needed to define whether there is a causal link between early-life EDC exposure and NAFLD development in humans. Elucidating the molecular mechanisms underlying development of NAFLD in the context of developmental EDC exposures may identify biomarkers for people at risk, as well as potential intervention and/or therapeutic opportunities for the disease.
... Although environmentally relevant in some areas, investigations considering only these levels of exposure have left much uncertainty about the potential effects of chronic exposures in the parts per billion range (Arteel et al. 2008;Reilly et al. 2014;Shi et al. 2014;Tan et al. 2011). In addition, our laboratory has demonstrated incidences of NAFLD in mice with low-level in utero exposure to arsenicals, and the present work aims to expand on those initial findings (Sanchez-Soria et al. 2014). The incidence of NAFLD is important to consider when examining cardiometabolic disease because NAFLD is thought to be the hepatic manifestation of metabolic syndrome (Paschos and Paletas 2009). ...
... The objective of this study was to examine the effects of exposure to low levels (100 ppb) of trivalent arsenic (As III ) on mice that were exposed during gestation, after weaning, or throughout life, with all mice being exposed to a Western-style diet after weaning. We have previously shown that low-level exposure to As III ] in utero was associated with incidence of fatty liver disease; this study aimed to reproduce these results on the background of a high-fat diet to determine whether As III exposure contributes to the incidence and severity of NAFLD (Sanchez-Soria et al. 2014). In addition, components of cardiometabolic syndrome were investigated to examine how these disease risk factors may be affected by low-level As III exposure. ...
... The links between As III exposure and NAFLD have been established for adult exposures at higher As III concentrations, but little is known about the mechanisms or the impact of low-level As III on fetal and early developmental periods (Arteel et al. 2008;Reilly et al. 2014;Shi et al. 2014;Tan et al. 2011). Our laboratory has previously demonstrated the incidence of NAFLD in mice with in utero exposures to 100 ppb As III (Sanchez-Soria et al. 2014) and, to our knowledge, is the only known example of this phenomenon. The present work has determined a mechanistic basis for the effects of arsenic on metabolic dysregulation and disease. ...
Chronic exposure to arsenicals, at various life stages and across a range of exposures, has been implicated in cardiometabolic disease and liver disease, but disease predisposition from developmental exposures remains unclear.
In utero and post-weaning As (III) exposure was examined on the background of a Western diet to determine whether As (III) affects metabolic disease.
Male Swiss Webster mice were exposed to 100 ppb As (III) in utero, after weaning, or both. Ad libitum access to a Western diet was provided after weaning, and the plasma metabolome, liver histopathology, liver enzyme activity, and gene expression were analyzed.
Hepatic lipid composition and histopathology revealed that developmental As (III) exposure exacerbated Western diet induced fatty liver disease. Continuous As (III) exposure increased cardiometabolic risk factors including increased body weight, insulin resistance, hyperglycemia, and plasma triglycerides. As (III) affected a decrease in the intermediates of glycolysis and the TCA cycle, while increasing ketones. Hepatic isocitrate dehydrogenase activity was also decreased, which confirms disruption of the TCA cycle. Developmental As (III) increased expression of genes involved in fatty acid synthesis, lipogenesis, inflammation, and packaging of triglycerides suggesting increased Acetyl-CoA load.
In utero and continuous early life exposure to As (III) disrupted normal metabolism and elevated the risk for fatty liver disease in mice maintained on a high fat diet. Our findings suggest that individuals exposed to As (III) during key developmental periods, and who remain exposed to As (III) on the background of a Western diet, may be at increased risk of metabolic disease later in life.
... iAs can cause metabolic disorders upon direct exposure [13]. The maternal effects of iAs have been characterized under the DOHaD paradigm [14][15][16][17][18][19][20][21][22][23][24]. These maternal iAs effects might be attributable to disrupted embryo development or altered maternal nurturing behaviors [25]. ...
... (2) We only tested the paternal effects of iAs because the maternal effects or prenatal exposure have been studied in animals and could be complicated by developmental disruptions in addition to the epigenetic effects [14][15][16][17][18][19][20][21][22][23][24]. ...
Background
Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences.
Methods
After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time.
Results
We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/β made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure.
Conclusions
These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions.
... [15][16][17] The transgenerational effects of iAs have not been studied in mammals, although the effect of early-life iAs exposure on later-life health has been characterized under the DOHaD paradigm. [18][19][20][21][22][23][24][25][26][27][28][29][30] We focused on an exclusive male-lineage exposure paradigm. This paradigm excludes most early-life developmental processes from prenatal or in utero exposures, [8] which allow us to study transgenerational effects within two generations. ...
... The outcome of iAs exposure is a mixture of the shortterm acute exposure and long-term effects due to early-life exposure that may impact prenatal and postnatal developmental processes. [23][24][25][26][27][28][29] Our study demonstrates robust intergenerational and transgenerational effects of male-lineage iAs exposure in the mammal for the first time. The distinct effects on different generations or sexes found in our study unveiled layers of complexity that are previously unknown in iAs toxicity. ...
The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross‐generational effects of iAs in an exclusive male‐lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6‐phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male‐lineage iAs exposure show increased adiposity, especially on a high‐calorie diet. These findings have unveiled sex‐ and generation‐specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene‐environment interactions. Inorganic arsenic (iAs) has sex‐ and generation‐specific heritable effects on metabolic physiology in mammals through the male germline lineage. Paternal exposure to iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males. F2 offspring from grand paternal iAs exposure show reduced adiposity. F3 offspring of the male‐lineage iAs exposure show increased adiposity.
... Using the in utero exposure model, Sanchez-Soria et al. (2014) reported that 36-week-old Swiss Webster male and female offspring of dams exposed to 100 ppb arsenic from embryonic day 6 until birth developed NAFLD (prominent micro-and macrovesicular steatosis). Furthermore, the offspring exhibited increased blood sugar levels and elevated low-density lipoprotein (LDL) and total cholesterol, potentially placing the mice at a higher risk of developing MetS (Sanchez-Soria et al. 2014). ...
... Using the in utero exposure model, Sanchez-Soria et al. (2014) reported that 36-week-old Swiss Webster male and female offspring of dams exposed to 100 ppb arsenic from embryonic day 6 until birth developed NAFLD (prominent micro-and macrovesicular steatosis). Furthermore, the offspring exhibited increased blood sugar levels and elevated low-density lipoprotein (LDL) and total cholesterol, potentially placing the mice at a higher risk of developing MetS (Sanchez-Soria et al. 2014). In another study, States et al. (2012) exposed atherosclerosis-prone ApoE −/− mice to 49 ppm arsenic in utero (gestation day 8 to term). ...
Abbreviations:
ALT: alanine aminotransferase; AMI: acute myocardial infarction; AST: aspartate aminotransferase; ATSDR: Agency for Toxic Substances and Disease Registry; CVD: cardiovascular disease; DMA: dimethylarsinate; DOHaD: Developmental Origins of Health and Disease; EPA: U.S. Environmental Protection Agency; ER-α: estrogen receptor alpha; HDL: high-density lipoprotein; HOMA-IR: homeostatic model assessment of insulin resistance; iAs: inorganic arsenic; LDL: low-density lipoprotein; MetS: metabolic syndrome; MMA: monomethylarsonate; NAFLD: non-alcoholic fatty liver disease; PND: postnatal day; ppb: parts per billion; ppm: parts per million; SAM: S-adenosylmethionine; USFDA: United States Food and Drug Administration.
... In humans, cord blood As levels, a marker of in utero exposure, have been associated with changes in DNA methylation of genes that are implicated in T2D and with altered expression of microR-NAs that are involved in T2D-related dysfunctions (Martin et al. 2017a). In laboratory studies, rats and mice exposed to iAs prenatally or during both pre-and postnatal windows developed diabetic phenotypes (Dávila-Esqueda et al. 2011;Bonaventura et al. 2017;Ditzel et al. 2016;Sanchez-Soria et al. 2014;Rodriguez et al. 2016). However, different phenotypes were associated with different levels of iAs exposure and with different exposure windows. ...
... We found that mice exposed to iAs during preconception and gestation periods developed an adverse metabolic phenotype characterized mainly by fasting hyperglycemia, insulin resistance, and fat accumulation. These phenotypic characteristics have also been reported in some of the previous prenatal exposure studies (Ditzel et al. 2016;Dávila-Esqueda et al. 2011;Bonaventura et al. 2017;Sanchez-Soria et al. 2014). We did not observe significant differences in glucose tolerance, as had been reported by Rodriguez et al. (2016) and Bonaventura et al. (2017). ...
Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied. The role of factors that modulate iAs metabolism and toxicity in adults and their potential to influence diabetogenic effects of prenatal iAs exposure are also unclear. The goal of this study was to determine if prenatal exposure to iAs impairs glucose metabolism in mice and if maternal supplementation with folate and methylcobalamin (B12) can modify this outcome. C57BL/6J dams were exposed to iAs in drinking water (0, 100, and 1000 µg As/L) and fed a folate/B12 adequate or supplemented diet from before mating to birth of offspring. After birth, dams and offspring drank deionized water and were fed the folate/B12 adequate diet. The metabolic phenotype of offspring was assessed over the course of 14 weeks. Male offspring from iAs-exposed dams fed the folate/B12-adequate diet developed fasting hyperglycemia and insulin resistance. Maternal folate/B12 supplementation rescued this phenotype but had only marginal effects on iAs metabolism in dams. The diabetogenic effects of prenatal iAs exposure in male offspring were not associated with changes in global DNA methylation in the liver. Only minimal effects of prenatal iAs exposure or maternal supplementation were observed in female offspring. These results suggest that prenatal iAs exposure impairs glucose metabolism in a sex-specific manner and that maternal folate/B12 supplementation may improve the metabolic phenotype in offspring. Further studies are needed to identify the mechanisms underlying these effects.
... For Permissions, please e-mail: journals.permissions@oup.com pathologies (Arteel et al., 2008;Sanchez-Soria et al., 2014;Tan et al., 2011). However, despite decades of research, arsenic's precise mechanism(s) of inducing disease remains poorly understood. ...
... Using a combination of novel and established methods including toxicological, biochemical, and genetic techniques, we report that arsenic results in metabolic shifts in vivo that are consistent with reported roles of arsenic in carcinogenesis (Zhao et al., 2014), metabolic syndrome (Ditzel et al., 2015;Shi et al., 2013), and other metabolism-related pathologies (Arteel et al., 2008;Sanchez-Soria et al., 2014;Tan et al., 2011). In particular, we report an arsenite-induced Warburg-like effect which has previously only been demonstrated in vitro, as well as previously unidentified alterations in mitochondrial respiration (reduced SRC and ATP-linked respiration, and increased proton leak). ...
Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research
studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly
understood. Mitochondria appear to be an important target of arsenic toxicity. The trivalent arsenical, arsenite, can induce
mitochondrial reactive oxygen species production, inhibit enzymes involved in energy metabolism, and induce aerobic glycolysis,
suggesting that metabolic dysfunction may be important in arsenic-induced disease. Here, using the model organism Caenorhabditis elegans and a novel metabolic inhibition assay, we report an in vivo induction of aerobic glycolysis following arsenite exposure. Furthermore, arsenite exposure induced severe mitochondrial
dysfunction, including altered pyruvate metabolism, reduced steady-state ATP levels, ATP-linked respiration and spare respiratory
capacity, and increased proton leak. We also found evidence that induction of autophagy is an important protective response
to arsenite exposure. Because these results demonstrate that mitochondria are an important in vivo target of arsenite toxicity, we hypothesized that deficiencies in mitochondrial electron transport chain genes, which cause
mitochondrial disease in humans, would sensitize nematodes to arsenite. In agreement with this, nematodes deficient in electron
transport chain complex I, II, and III, but not ATP synthase, were sensitive to arsenite exposure, thus identifying a novel
class of gene-environment interactions that warrant further investigation in the human populace.
... Diet may negatively affect arsenic-associated effects on fat metabolism and liver function. Previous work has shown that arsenic exposure is associated with high cholesterol, liver inflammation, and liver steatosis (Sanchez-Soria et al. 2014;Shi et al. 2014). Co-exposure to a high fat Western diet and arsenic in mice exacerbated high-fat diet effects on the liver (e.g., increased size and steatosis), resulting in degeneration that was more severe and widespread than in the controls without arsenic exposure (Sanchez-Soria et al. 2014). ...
... Previous work has shown that arsenic exposure is associated with high cholesterol, liver inflammation, and liver steatosis (Sanchez-Soria et al. 2014;Shi et al. 2014). Co-exposure to a high fat Western diet and arsenic in mice exacerbated high-fat diet effects on the liver (e.g., increased size and steatosis), resulting in degeneration that was more severe and widespread than in the controls without arsenic exposure (Sanchez-Soria et al. 2014). Mice exposed to arsenic in utero were affected more strongly than mice exposed later in life. ...
Background:
Exposure to inorganic and organic arsenic compounds is a major public health problem that affects hundreds of millions of people worldwide. Exposure to arsenic is associated with cancer and non-cancer effects in nearly every organ in the body, and evidence is mounting for health effects at lower levels of arsenic exposure than previously thought. Building from a tremendous knowledge base with more than 1,000 scientific papers published annually with "arsenic" in the title, the question becomes, what questions would best drive future research directions?
Objectives:
The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines.
Methods:
The National Institutes of Health's National Institute of Environmental Health Sciences Superfund Research Program convened a workshop to identify emerging issues and research needs to address the multi-faceted challenges related to arsenic and environmental health. This review summarizes information captured during the workshop.
Discussion:
More information about aggregate exposure to arsenic is needed, including the amount and forms of arsenic found in foods. New strategies for mitigating arsenic exposures and related health effects range from engineered filtering systems to phytogenetics and nutritional interventions. Furthermore, integration of 'omics data with mechanistic and epidemiological data is a key step towards the goal of linking biomarkers of exposure and susceptibility to disease mechanisms and outcomes.
Conclusions:
Promising research strategies and technologies for arsenic exposure and adverse health effect mitigation are being pursued, and future research is moving toward deeper collaborations and integration of information across disciplines to address data gaps.
... Intrauterine exposure to arsenic has been shown to influence the developmental programming of DM. Experimental studies using animal models demonstrated that in utero contamination by arsenic raised HOMA-IR in offsprings [18,33,37,51,99]. This observation was accompanied by histopathological findings consistent with non-alcoholic fatty liver disease [18, 33, 37, 51, 99], which is intimately related to IR. Prenatal arsenic pollution is linked to distorted cord blood gene expression, DNA, and miRNA methylation profiles in pathways linked to diabetes (Akt signaling pathway, miRNAs miR-107, and miR-20b), according to birth cohorts of expectant mothers exposed to the substance in Mexico, New Hampshire, and Taiwan [9,59,76,90,97]. ...
Studies have implicated arsenic exposure in various pathological conditions, including metabolic disorders, which have become a global phenomenon, affecting developed, developing, and under-developed nations. Despite the huge risks associated with arsenic exposure, humans remain constantly exposed to it, especially through the consumption of contaminated water and food. This present study provides an in-depth insight into the mechanistic pathways involved in the metabolic derangement by arsenic. Compelling pieces of evidence demonstrate that arsenic induces metabolic disorders via multiple pathways. Apart from the initiation of oxidative stress and inflammation, arsenic prevents the phosphorylation of Akt at Ser473 and Thr308, leading to the inhibition of PDK-1/Akt insulin signaling, thereby reducing GLUT4 translocation through the activation of Nrf2. Also, arsenic downregulates mitochondrial deacetylase Sirt3, decreasing the ability of its associated transcription factor, FOXO3a, to bind to the agents that support the genes for manganese superoxide dismutase and PPARg co-activator (PGC)-1a. In addition, arsenic activates MAPKs, modulates p53/ Bcl-2 signaling, suppresses Mdm-2 and PARP, activates NLRP3 inflammasome and caspase-mediated apoptosis, and induces ER stress, and ox-mtDNA-dependent mitophagy and autophagy. More so, arsenic alters lipid metabolism by decreasing the presence of 3-hydroxy-e-methylglutaryl-CoA synthase 1 and carnitine O-octanoyl transferase (Crot) and increasing the presence of fatty acid-binding protein-3 mRNA. Furthermore, arsenic promotes atherosclerosis by inducing endothelial damage. This cascade of pathophysiological events promotes metabolic derangement. Although the pieces of evidence provided by this study are convincing, future studies evaluating the involvement of other likely mechanisms are important. Also, epidemiological studies might be necessary for the translation of most of the findings in animal models to humans.
... from metabolites of neurotransmitters and hormones may be also an important etiologic factor in the development of lipid disorders and liver disease. This has been confirmed by the studies showing that arsenic exposure was associated with liver inflammation and steatosis as well as with a high cholesterol level [42][43]. It has been also stated that arsenic alters lipid metabolism in a pattern that suggests disruption of the tricarboxylic acid (TCA) cycle and increased ketogenesis [44]. ...
Background:
Almost every organ in the human body can be affected by arsenic (As) exposure associated with various industrial processes, as well as with contaminated food, drinking water and polluted air. Much is known about high exposure to inorganic As but there is little data on the metabolic changes connected to a low exposure e.g. in people living in smelter areas.
Objectives:
The objectives of the study were: (1) characterise urinary concentration of total arsenic (AsT) in Polish inhabitants of the vicinity of a copper smelter area, (2) speciation analysis of various forms of arsenic in girls (GL), boys (BL), women (WL) and men (ML) with a slightly elevated AsT concentration and age/sex matched groups with a substantially higher AsT concentration, (GH, BH, WH and MH - respectively), (3) comparison of metabolomics profiles of urine between the age/sex matched people with low and high AsT concentrations.
Methods:
Urine samples were analysed for total arsenic and its chemical forms (AsIII; AsV, methylarsonic acid, dimethylarsinic acid, arsenobetaine) using HPLC-ICP-MS. Untargeted metabolomics analysis of the urine samples was performed using UPLC system connected to Q-TOF-MS equipped with an electrospray source. The XCMS Online program was applied for feature detection, retention time correction, alignment, statistics, annotation and identification. Potentially identified compounds were fragmented and resulting spectra were compared to the spectra in the Human Metabolome Database.
Results:
Urine concentration of AsT was, as follows: GL 16.40 ± 0.83; GH 115.23 ± 50.52; BL 16.48 ± 0.83; BH 95.00 ± 50.03; WL 16.93 ± 1.21; WH 170.13 ± 96.47; ML 16.91 ± 1.20; MH 151.71 ± 84.31 μg/l and percentage of arsenobetaine in AsT was, as follows: GL 65.5 ± 13.8%, GH 87.2 ± 4.7%, BL 59.8 ± 12.5%, BH 90.5 ± 2.4%, WL 50.8 ± 14.1%, WH 90.4 ± 3.5%, ML 53.3 ± 10.0%, MH 74.6 ± 20.2%. In the people with low and high AsT concentrations there were significant differences in the intensity of signal (is.) from numerous compounds being metabolites of neurotransmitters, nicotine and hormones transformation (serotonin in the girls and women; catecholamines in the girls, boys and women; mineralocorticoids and glucocorticoids in the boys, androgens in the women and men and nicotine in the boys, women and men). These changes might have been associated with higher is. from metabolites of leucine, tryptophan, purine degradation (in the GH, WH), urea cycle (in the WH and MH), glycolysis (in the WH) and with lower is. from metabolites of tricarboxylic acid cycle (in the BH) in comparison with low AsT matched groups. In the MH vs. ML higher is. from metabolite of lipid peroxidation (4-hydroxy-2-nonenal) was observed. Additionally, the presence of significant differences was reported in is. from food components metabolites, which might have modulated the negative effects of As (vitamin C in the girls, boys and men, vitamin B6 in the girls, boys and women as well as phenolic compounds in the boys and girls). We hypothesize that the observed higher is. from metabolites of sulphate (in MH) and glucoronate degradation (in BH, WH and MH) than in the matched low AsT groups may be related to the impaired glucuronidation and sulfonation and higher is. from catecholamines, nicotine and hormones.
Conclusion:
Our results indicated that even a low exposure to As is associated with metabolic changes and that urine metabolomics studies could be a good tool to reflect their wide spectrum connected to specific environmental exposure to As, e.g. in smelter areas.
... Chronic exposure to Cd (Cadmium) can have effects, such as lung cancer, prostatic proliferative lesions, bone fractures, kidney dysfunction and hypertension (Om and Shim, 2007). High levels of Pb (Plumbum) exposure remain ubiquitous and cause numerous adverse health effects on the nervous system (Kamal et al., 2016), and Pb can cause diabetes mellitus, impair cognitive development and cause cardiac disorders (Sanchez-Soria et al., 2014). The main sources of heavy metals in the environment are geogenic and anthropogenic. ...
The objective of this study was to investigate heavy metal contamination in four major vegetable bases and determine the health risks of residents in the vicinity of the highly urbanized city Urumqi in Xinjiang, China. In this paper, we determined the contents of six heavy metals (i.e., As, Zn, Cd, Cr, Hg, and Pb) in surface soil and groundwater to evaluate the levels of heavy metal pollution and human health risks using the pollution index (PI), the Nemerow integrated pollution index (NIPI), the ecological risk factor (Eir), risk index (RI) and the health risk assessment model. The results showed that (1) The PI, NIPI, the ecological risk factor and risk index indicated that Cd and Hg were the primary pollutants in Sishihu village. These indices suggested moderate to slightly heavy potential ecological risks. In Anningqu town, Hg and Cd led to high levels of pollution and posed slightly heavy potential ecological risks. In Qinggedahu village, it was concluded that the metals Zn, Cr, Cd, Hg, and Pb caused moderate to heavy pollution. In Liushihu village, the pollution trends in the area were low. The results of the pollution level of the irrigation well water (i.e., groundwater) indicated that the well water was considerably safer than the soil, but Cr posed a slight pollution risk. (2) The non-carcinogenic risks for adults based on the HI values of these four vegetable bases were <1. However, when considering the non-carcinogenic risks for children, the HI values were larger than 1 in all areas, indicating the local children have a higher potential non-carcinogenic risk. In addition, CR (Carcinogenic risk) from dermal contact with the vegetables bases did not pose a high risk for residents. However, for adults, the carcinogenic risk posed by Arsenic (As) through trough inhalation was the primary pathway of exposure in three of the vegetable bases, generally in the order of Qinggedahu village > Sishihu village > Anningqu town. For children, the carcinogenic risks posed by As through trough inhalation and ingestion were the main exposure pathways. From the TCR results, it can be seen that in Sishihu village, Anningqu town, and Qinggedahu village, the TCR values for adults and children were >1 × 10-4 (unitless), and this degree of carcinogenic risk is unacceptable. (3) The identification of risk sources determined the main pollution sources affecting the vegetable bases were human activities and natural sources. Anthropogenic activities were most often related to traffic pollution sources and agricultural pollution sources, such as the irrational use of pesticides and fertilizers and stock farming. The results are important for designing remediation scenarios to control the spread of contamination as well as for serving as a reference point for soil environmental protection efforts in this region.
... Of the toxicants tested, arsenite may have the highest potential for human health relevance, as over 140 million people worldwide are chronically exposed to arsenite via consumption of contaminated drinking water (Chowdhury et al., 2006;Ravenscroft et al., 2009). Although chronic arsenite exposure is associated with cancer (Gilbert-Diamond et al., 2013;Karagas et al., 2004;Marshall et al., 2007;Yu et al., 2006), and other metabolism-related pathologies (Ditzel et al., 2015;Sanchez-Soria et al., 2014;Shi et al., 2013), the precise mechanisms underlying pathogenesis are complex, and remain poorly understood. We also demonstrate that arsenite disrupts mitochondrial energy metabolism in fusion (fzo-1, eat-3)-deficient nematodes, while increasing mitochondrial function in wild-type nematodes, and has minimal effect on mitochondrial function in fission (drp-1)-deficient nematodes. ...
Mitochondrial fission, fusion, and mitophagy are interlinked processes that regulate mitochondrial shape, number, and size, as well as metabolic activity and stress response. The fundamental importance of these processes is evident in the fact that mutations in fission (DRP1), fusion (MFN2, OPA1), and mitophagy (PINK1, PARK2) genes can cause human disease (collectively >1/10,000). Interestingly, however, the age of onset and severity of clinical manifestations varies greatly between patients with these diseases (even those harboring identical mutations), suggesting a role for environmental factors in the development and progression of certain mitochondrial diseases. Using the model organism Caenorhabditis elegans, we screened ten mitochondrial toxicants (2, 4-dinitrophenol, acetaldehyde, acrolein, aflatoxin B1, arsenite, cadmium, cisplatin, doxycycline, paraquat, rotenone) for increased or decreased toxicity in fusion (fzo-1, eat-3)-, fission (drp-1)-, and mitophagy (pdr-1, pink-1)-deficient nematodes using a larval growth assay. In general, fusion-deficient nematodes were the most sensitive to toxicants, including aflatoxin B1, arsenite, cisplatin, paraquat, and rotenone. Because arsenite was particularly potent in fission- and fusion-deficient nematodes, and hundreds of millions of people are chronically exposed to arsenic, we investigated the effects of these genetic deficiencies on arsenic toxicity in more depth. We found that deficiencies in fission and fusion sensitized nematodes to arsenite-induced lethality throughout aging. Furthermore, low-dose arsenite, which acted in a “mitohormetic” fashion by increasing mitochondrial function (in particular, basal and maximal oxygen consumption) in wild-type nematodes by a wide range of measures, exacerbated mitochondrial dysfunction in fusion-deficient nematodes. Analysis of multiple mechanistic changes suggested that disruption of pyruvate metabolism and Krebs cycle activity underlie the observed arsenite-induced mitochondrial deficits, and these disruptions are exacerbated in the absence of mitochondrial fusion. This research demonstrates the importance of mitochondrial dynamics in limiting arsenite toxicity by permitting mitochondrial adaptability. It also suggests that individuals suffering from deficiencies in mitodynamic processes may be more susceptible to the mitochondrial toxicity of arsenic and other toxicants.
... In previous research Camenisch and colleagues studied metabolic disease risk in mice exposed prenatally to low-level arsenic. 9 In those experiments, offspring of female mice that drank water containing 100 ppb sodium arsenite during pregnancy developed nonalcoholic fatty liver disease and other signs of heightened risk for metabolic syndrome, a constellation of symptoms associated with diabetes and cardiovascular disease in humans. ...
Background:
Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults.
Objectives:
The present study examined how oral iAs administration to neonatal mice impacts the intestinal tract, which acts as an early mediator for NAFLD.
Methods:
Neonatal mice were treated with a single dose of iAs via oral gavage. Effects on the small intestine were determined by histological examination, RNA sequencing, and biochemical analysis. Serum lipid profiling was analyzed by fast protein liquid chromatography (FPLC), and hepatosteatosis was characterized histologically and biochemically. Liver X receptor-alpha (LXRα) knockout (Lxrα-/-) mice and liver-specific activating transcription factor 4 (ATF4)-deficient (Atf4ΔHep) mice were used to define their roles in iAs-induced effects during the neonatal stage.
Results:
Neonatal mice exposed to iAs via oral gavage exhibited accumulation of dietary fat in enterocytes, with higher levels of enterocyte triglycerides and free fatty acids. These mice also showed accelerated enterocyte maturation and a longer small intestine. This was accompanied by higher levels of liver-derived very low-density lipoprotein and low-density lipoprotein triglycerides, and a lower level of high-density lipoprotein cholesterol in the serum. Mice exposed during the neonatal period to oral iAs also developed hepatosteatosis. Compared with the control group, iAs-induced fat accumulation in enterocytes became more significant in neonatal Lxrα-/- mice, accompanied by accelerated intestinal growth, hypertriglyceridemia, and hepatosteatosis. In contrast, regardless of enterocyte fat accumulation, hepatosteatosis was largely reduced in iAs-treated neonatal Atf4ΔHep mice.
Conclusion:
Exposure to iAs in neonatal mice resulted in excessive accumulation of fat in enterocytes, disrupting lipid homeostasis in the serum and liver, revealing the importance of the gut-liver axis and endoplasmic reticulum stress in mediating iAs-induced NAFLD at an early age. https://doi.org/10.1289/EHP12381.
Developmental arsenic exposure leads to increased susceptibility to liver diseases including nonalcoholic fatty liver diseases, but the mechanism is incompletely understood. In this study, C57BL/6 J mice were used to establish a lifetime arsenic exposure model covering developmental stage. We found that arsenic-exposed offspring in later life showed hepatic lipid deposition and increased triglyceride content. Despite no significant hepatic pathological changes in the offspring at weaning, 86 miRNAs and 136 mRNAs were differentially expressed according to miRNA array and mRNA sequencing. The differentially expressed genes (DEGs) were crossed with the target genes predicted by differentially expressed miRNAs (DEMs), and 47 differentially expressed target genes (DETGs) were obtained. Functional annotation suggested that lipid metabolism related pathways were significantly enriched. The pivotal regulator in the four major pathways to maintain liver lipid homeostasis were further determined, with significant alterations found in FABP5, SREBP1, ACOX1 and EHHADH. Of note, miRNA-mRNA integration analysis revealed that miR-7118-5p, miR-7050-5p, miR-27a/b-3p, and miR-103-3p acted as key regulators of fatty acid metabolism genes. Taken together, miRNA-mRNA integration analysis indicates that the lipid metabolism pathway in the liver of weaned mice was dysregulated by developmental arsenic exposure, which may contributes to the development of NAFLD in later life.
This study analyzed five heavy elements (HEs), including cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), and arsenic (As), in fresh vegetables (i.e., legume, rhizome and potato, gourd, bulb, solanaceous fruit, leafy, and brassica; total: 7214) collected from 31 provinces in China from 2016 to the first half of 2017. By analyzing the concentration level of the five HEs in seven regions (the Northeast, North China, East China, South China, Central China, the Northwest, and the Southwest), except for As, average HEs concentrations were higher in the Southwest than that in the other six regions. According to the maximum permissible limit (MPL), the highest rate of HEs concentration above the MPL was found in the Southwest (11.038%). Analysis of variance (ANOVA) showed varying degrees of variability between regions and categories. By using principal component analysis (PCA), it was found that two principal components account for 73.79% of the total variance in the data. Together with hierarchical cluster analysis (HCA), concluded that Tibet was significantly different from the other 30 provinces. By calculating estimated daily intake (EDI) and the target hazard quotient (THQ), the EDI of Cr in the Southwest was the highest, with results of 1.2119 μg/kg/day for children and 0.8073 μg/kg/day for adults. North China had the highest total target hazard quotient (TTHQ) for HEs in vegetables ingested by children, with a result of 0.933.
The activation of hepatic stellate cells (HSCs) is a key event in the development of hepatic fibrosis caused by arsenic. However, it is unclear how arsenic induces the activation of HSCs. In the present study, we found that arsenic trioxide (As2O3) induced liver tissue damage, stimulated autophagy and HSCs activation, and increased collagen accumulation in the liver of mice. Supplemented with taurine (Tau) attenuated the changes mentioned above caused by As2O3. In human hepatic stellate cell line LX-2 cells, we found that As2O3-induced activation of HSCs was autophagy-dependent, and we found that peroxisome proliferator activated receptors alpha (PPARα) played an important role in arsenic-induced HSCs activation. In addition, inhibiting autophagy and PPARα alleviated the activation of HSCs and lipid droplet loss induced by As2O3. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy and PPARα expression, and activation of the HSCs. Our results indicated that autophagy was regulated by PPARα and was involved in lipid droplet loss during the activation of HSCs. Tau alleviated As2O3-induced HSCs activation by inhibiting the PPARα/autophagy pathway. These findings give an innovative insight into the association of PPARα, autophagy, the activation of HSCs and hepatic fibrosis induced by As2O3.
Although it is generally believed that the developing fetus is principally exposed to inorganic arsenic and the methylated metabolites from the maternal metabolism of arsenic, little is known about whether the developing embryo can autonomously metabolize arsenic. This study investigates inorganic arsenic methylation by murine embryonic organ cultures of the heart, lung, and liver. mRNA for AS3mt, the gene responsible for methylation of arsenic, was detected in all embryonic tissue types studied. In addition, methylated arsenic metabolites were generated by all three tissue types. The fetal liver explants yielded the most methylated arsenic metabolites (∼7% of total arsenic/48 h incubation) while the heart, and lung preparations produced slightly greater than 2% methylated metabolites. With all tissues the methylation proceeded mostly to the dimethylated arsenic species. This has profound implications for understanding arsenic-induced fetal toxicity, particularly if the methylated metabolites are produced autonomously by embryonic tissues.
Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic.
Many plants and animals are capable of developing in a variety of ways, forming characteristics that are well adapted to the environments in which they are likely to live. In adverse circumstances, for example, small size and slow metabolism can facilitate survival, whereas larger size and more rapid metabolism have advantages for reproductive success when resources are more abundant. Often these characteristics are induced in early life or are even set by cues to which their parents or grandparents were exposed. Individuals developmentally adapted to one environment may, however, be at risk when exposed to another when they are older. The biological evidence may be relevant to the understanding of human development and susceptibility to disease. As the nutritional state of many human mothers has improved around the world, the characteristics of their offspring--such as body size and metabolism--have also changed. Responsiveness to their mothers' condition before birth may generally prepare individuals so that they are best suited to the environment forecast by cues available in early life. Paradoxically, however, rapid improvements in nutrition and other environmental conditions may have damaging effects on the health of those people whose parents and grandparents lived in impoverished conditions. A fuller understanding of patterns of human plasticity in response to early nutrition and other environmental factors will have implications for the administration of public health.
The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood "undernutrition."
We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study.
The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001).
There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders.
Low birth weight is a risk factor for coronary heart disease. It is uncertain how postnatal growth affects disease risk.
We studied 8760 people born in Helsinki from 1934 through 1944. Childhood growth had been recorded. A total of 357 men and 87 women had been admitted to the hospital with coronary heart disease or had died from the disease. Coronary risk factors were measured in a subset of 2003 people.
The mean body size of children who had coronary events as adults was below average at birth. At two years of age the children were thin; subsequently, their body-mass index (BMI) increased relative to that of other children and had reached average values by 11 years of age. In simultaneous regressions, the hazard ratios associated with a 1 SD increase in BMI were 0.76 (95 percent confidence interval, 0.66 to 0.87; P<0.001) at 2 years and 1.14 (95 percent confidence interval, 1.00 to 1.31; P=0.05) at 11 years among the boys. The corresponding figures for the girls were 0.62 (95 percent confidence interval, 0.46 to 0.82; P=0.001) and 1.35 (95 percent confidence interval, 1.02 to 1.78; P=0.04). Low BMI at 2 years of age and increased BMI from 2 to 11 years of age were also associated with raised fasting insulin concentrations (P<0.001 for both).
On average, adults who had a coronary event had been small at birth and thin at two years of age and thereafter put on weight rapidly. This pattern of growth during childhood was associated with insulin resistance in later life. The risk of coronary events was more strongly related to the tempo of childhood gain in BMI than to the BMI attained at any particular age.
Women live longer than men and develop cardiovascular disease (CVD) at an older age. The metabolic syndrome represents a major risk factor for the development of CVD, and gender1 differences in this syndrome may contribute to gender differences in CVD.
In recent years, the metabolic syndrome has been more prevalent in men than in women. Prevalence is increasing and this increase has been steeper in women, particularly in young women, during the last decade. The contributions of the different components of the metabolic syndrome differ between genders and in different countries.
In a recent survey in Germany, 40% of the adult population had been diagnosed with disturbed glucose tolerance or type 2 diabetes. Undiagnosed diabetes was more frequent in men than in women, and risk factors for undiagnosed diabetes differed between the sexes. Worldwide, in individuals with impaired glucose tolerance, impaired fasting glucose was observed more frequently in men, whereas impaired glucose tolerance occurred relatively more often in women. Lipid accumulation patterns differ between women and men. Premenopausal women more frequently develop peripheral obesity with subcutaneous fat accumulation, whereas men and postmenopausal women are more prone to central or android obesity. In particular, android obesity is associated with increased cardiovascular mortality and the development of type 2 diabetes. Visceral adipocytes differ from peripheral adipocytes in their lipolytic activity and their response to insulin, adrenergic and angiotensin stimulation and sex hormones. Visceral fat is a major source of circulating free fatty acids and cytokines, which are directly delivered via the portal vein to the liver inducing insulin resistance and an atherogenic lipid profile. Inflammation increases cardiovascular risk particularly in women. A relatively greater increase in cardiovascular risk by the appearance of diabetes in women has been reported in many studies.
Thus, the presently available data suggest that the pathophysiology of the metabolic syndrome and its contribution to the relative risk of cardiovascular events and heart failure show gender differences, which might be of potential relevance for prevention, diagnostics, and therapy of the syndrome.
Mineral deficiencies can cause impaired insulin release and insulin resistance. This study was conducted to investigate the relationship between hair mineral concentrations and insulin resistance in patients with metabolic syndrome (MS). A total of 456 subjects (161 patients with MS and 295 subjects without MS) were reviewed, and fasting plasma glucose, triglycerides, HDL-cholesterol, homeostasis assessment model-insulin resistance (HOMA-IR), and hair mineral concentrations were analyzed. While hair sodium and potassium concentrations were significantly higher, the hair calcium, magnesium, and zinc concentrations were lower in the MS group than in the control group. Regarding toxic element measurements, the hair arsenic (As) and lead (Pb) concentrations were higher in the MS group than in the control group. The results of multiple regression analysis, after adjusting for age, showed significant relationships between the Na/Mg and Ca/P ratios and HOMA-IR (R (2) = 0.109, p < 0.05). The Ca, Na, K, and B concentrations were also associated with HOMA-IR (R (2) = 0.116, p < 0.05). The hair Na concentration was significantly associated with MS, even after adjusting for age, visceral adipose tissue, and HOMA-IR (OR 1.020; 95 % CI 1.001-1.040; p = 0.036). Our findings suggest that hair mineral concentrations, such as calcium, magnesium, zinc, sodium, and potassium concentrations, may play a role in the development of insulin resistance.
Metabolic syndrome (MetS) is a vascular risk factor with prevalence in the general population of 17-25%.
To determine the prevalence of MetS in patients with diabetes mellitus (DM).
A total of 200 patients [18% type 1 (T1DM), 82% type 2 (T2DM)] attending for annual review were studied. Standard blood tests were requested. Blood pressure and waist circumference were measured. Adult Treatment Panel III (ATP III) criteria for diagnosis of MetS were applied.
A total of 122 (61%) patients had MetS. More patients with T2DM (69.5%) than TIDM (22.2%) had MetS. Despite treatment of DM (100%), hypertension (69.5%) and dyslipidaemia (48.3%), 114 patients (57%) still met the criteria for MetS at time of study.
Most T2DM patients have MetS but it is uncommon in T1DM. Despite treatment, almost half of patients still met the criteria for MetS. Aggressive treatment of MetS components is required to reduce cardiovascular risk in DM.
The prevalence of and the risk factors for fatty liver have not undergone a formal evaluation in a representative sample of the general population. We therefore performed a cross-sectional study in the town of Campogalliano (Modena, Italy), within the context of the Dionysos Project. Of 5,780 eligible persons aged 18 to 75 years, 3,345 (58%) agreed to participate in the study. Subjects with suspected liver disease (SLD), defined on the basis of elevated serum alanine aminotransferase (ALT) and gamma-glutamyl-transferase (GGT) activity, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)-RNA positivity, were matched with randomly selected subjects of the same age and sex without SLD. A total of 311 subjects with and 287 without SLD underwent a detailed clinical, laboratory, and anthropometrical evaluation. Fatty liver was diagnosed by ultrasonography, and alcohol intake was assessed by using a 7-day diary. Multinomial logistic regression was used to detect risk factors for normal liver versus nonalcoholic fatty liver disease (NAFLD) and for alcoholic fatty liver (AFLD) versus NAFLD. The prevalence of NAFLD was similar in subjects with and without SLD (25 vs. 20%, P = .203). At multivariable analysis, normal liver was more likely than NAFLD in older subjects and less likely in the presence of obesity, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and systolic hypertension; AFLD was more likely than NAFLD in older subjects, males, and in the presence of elevated GGT and hypertriglyceridemia, and less likely in the presence of obesity and hyperglycemia. In conclusion, NAFLD is highly prevalent in the general population, is not associated with SLD, but is associated with many features of the metabolic syndrome.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.
Insulin (51 amino acids, 5808 Da) is synthesized from its precursors preproinsulin and proinsulin (hPI; 86 amino acids) in the β cells of the pancreatic islets of Langerhans. A human insulin molecule is chemically homogeneous, consisting of 2 polypeptide chains, the A chain (21 amino acids) and B chain (30 amino acids), connected by 2 disulfide bonds (A7-B7 and A20-B19); a 3rd disulfide bond links the A6 and A11 residues. In serum, insulin circulates in a free form (not bound to carrier proteins) together with small quantities of its precursors, mainly intact hPI and des (31,32) split hPI (hPI cleaved at the junction between the B chain and C-peptide linking the A and B chains in the hPI molecule). Des (64,65) split hPI (hPI cleaved at the junction between the A chain and C-peptide) is a minor component of hPIs in serum (1).
Insulin is the only hypoglycemic hormone. Its measurement in serum plays a central role in the assessment of β-cell secretion and insulin resistance. Ideally, an insulin assay should be sensitive, specific, and applicable to a large number of samples. It should also be standardized to be efficiently used in large multicenter clinical studies and considered in guidelines.
Among insulin assay methods, only immunoassays are applicable to large numbers of samples. The 1st RIA for human insulin, described in 1959 by Yalow and Berson (2), relied on competitive binding of human insulin in plasma samples or calibrators and 131I-labeled bovine insulin to guinea-pig anti–bovine insulin polyclonal antibodies. Separation of the bound and free fractions was performed by chromatoelectrophoresis. Later the availability of human insulin in larger quantities (3) allowed the production of guinea-pig anti–human insulin antibodies, and an antibody precipitation technique made the assay easier to use. Except for 1 assay, RIAs detect both insulin and …
The association between small size at birth and impaired glucose regulation later in life is well established in persons born at term. Preterm birth with very low birth weight (<1500 g) is also associated with insulin resistance in childhood. If insulin resistance persists into adulthood, preterm birth with very low birth weight also may be associated with an increased risk of disease in adulthood. We assessed glucose tolerance and insulin sensitivity and measured serum lipid levels and blood pressure in young adults with very low birth weight.
We performed a standard 75-g oral glucose-tolerance test, measuring insulin and glucose concentrations at baseline and at 120 minutes in 163 young adults (age range, 18 to 27 years) with very low birth weight and in 169 subjects who had been born at term and were not small for gestational age. The two groups were similar with regard to age, sex, and birth hospital. We measured blood pressure and serum lipid levels, and in 150 very-low-birth-weight subjects and 136 subjects born at term, we also measured body composition by means of dual-energy x-ray absorptiometry.
As compared with the subjects born at term, the very-low-birth-weight subjects had a 6.7% increase in the 2-hour glucose concentration (95% confidence interval [CI], 0.8 to 12.9), a 16.7% increase in the fasting insulin concentration (95% CI, 4.6 to 30.2), a 40.0% increase in the 2-hour insulin concentration (95% CI, 17.5 to 66.8), an 18.9% increase in the insulin-resistance index determined by homeostatic model assessment (95% CI, 5.7 to 33.7), and an increase of 4.8 mm Hg in systolic blood pressure (95% CI, 2.1 to 7.4). Adjustment for the lower lean body mass in the very-low-birth-weight subjects did not attenuate these relationships.
Young adults with a very low birth weight have higher indexes of insulin resistance and glucose intolerance and higher blood pressure than those born at term.