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Increased viability of endometrial cells by in vitro treatment with di-(2-ethylhexyl) phthalate
Abstract
Based on the findings of several reports that have shown an increased plasma level of di-(2-ethylhexyl) phthalate (DEHP) in women with endometriosis, the present study was designed to evaluate whether in vitro treatment with DEHP can increase viability of endometrial cells. Utilizing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay, fluorescent activated cell sorter analysis, and microscopic evaluation after Hoechst staining, we revealed that in vitro treatment with DEHP leads to increased viability of Ishikawa cells as well as endometrial stromal cells in serum-free condition and following exposure to hydrogen peroxide, which suggests that exposure to phthalate might play a role in the establishment of endometriosis.
... These concentrations were similar to those reported in women with endometriosis. The DEHP-treated samples showed an increase in cell viability, suggesting that this DEHP-induced survival mechanism may be related to the development of endometriosis since cell survival is a key factor in retrograde menstruation as a first event in endometriosis process (Kim et al., 2010). As mentioned above, the estrous cycle is driven by a hormonal balance, mainly E2 and P4, thinly regulated in the endometrium (Marquardt et al., 2019). ...
... Furthermore, in vitro studies have shown that DEHP increases the viability of the endometrial cells of healthy women by increasing their resistance to oxidative stress induced by hydrogen peroxide treatment. This suggests that this survival mechanism is involved in the proliferation of ectopic endometrial tissue and contributes to the development of endometriosis (Kim et al., 2010). Another study on endometrial cells showed that DEHP treatment increased the activity of matrix metalloproteinases MMP-2 and MMP-9, a family of proteins sensitive to oxidative stress , and enhanced cell proliferation, resistance to apoptosis, and cellular invasiveness through Erk phosphorylation and increased expression of PAK-4 (p21-activated kinase 4) (Chou and Tzeng, 2021). ...
... Unfortunately, the accurate DEHP mechanism that explains this second result is not known. However, it has been suggested that DEHP may likely alter the intracellular events that precede the initiation of cell death pathways (Kim et al., 2010). Further studies are needed to confirm these paradoxical findings and to understand how DEHP contributes to female fertility disorders. ...
... Several studies have reported cellular aberrations in endometrial cells obtained from both disease free women and those suffering from endometriosis after acute DEHP exposure [16][17][18][19][20]. Acute DEHP exposure was found to increase cell viability, oxidative stress, and invasive capacity, altering the inflammatory response and steroid signaling in endometrial cells; these abnormalities are shared with both eutopic and ectopic endometrial cells in endometriosis [16][17][18][19][20]. ...
... Several studies have reported cellular aberrations in endometrial cells obtained from both disease free women and those suffering from endometriosis after acute DEHP exposure [16][17][18][19][20]. Acute DEHP exposure was found to increase cell viability, oxidative stress, and invasive capacity, altering the inflammatory response and steroid signaling in endometrial cells; these abnormalities are shared with both eutopic and ectopic endometrial cells in endometriosis [16][17][18][19][20]. In addition, in mouse models of endometriosis, exposure to DEHP seemed to increase the size and the proliferation of the ectopic endometrial implants [16]. ...
... Our observations conflict with previous studies with an experimental design comparable to ours, with acute exposure (24-48 h) to DEHP doses in the picomolar to micromolar range. In these previous studies, the authors essentially observed an increase in the inflammatory response and invasiveness of the exposed cells [16,17,[19][20][21], which we intended to replicate in our study. Although we were able to recapitulate the invasiveness increase after acute DEHP exposure, we were not able to induce the inflammatory, angiogenic, morphogenic, epigenetic, and steroid receptor expression alterations described in endometrial cells from women with this pathology. ...
Environmental factors that have been linked to an increased endometriosis risk include exposure to di-(2-ethylhexyl)-phthalate (DEHP), an endocrine disruptor. This study aims to investigate whether DEHP in vitro exposure in primary endometrial stromal cells (EnSC), primary endometrial epithelial cells (EnEC), and the human endometrial adenocarcinoma cell line Ishikawa properly mimics alterations described in the eutopic endometrium of women with endometriosis. Primary EnSC and EnEC, isolated from six fertile egg donors, and Ishikawa cells were exposed to DEHP (0.1, 1, and 10 µM) and were assessed for viability, endometriosis markers (IL-6, VEGF-A, HOXA10, EZH2, and LSD1), steroid receptor gene expressions (ER-1, ER-2, PR-T, PR-B, and PGRMC1), and invasive capacity. Viability after 72 h of DEHP exposure was not significantly affected. None of the endometriosis markers studied were altered after acute DEHP exposure, nor was the expression of steroid receptors. The invasive capacity of EnSC was significantly increased after 10 µM of DEHP exposure. In conclusion, acute DEHP exposure in primary endometrial cells does not fully phenocopy the changes in the viability, expression of markers, or steroidal receptors described in endometriosis. However, the significant increase in EnSC invasiveness observed after DEHP exposure could be a link between DEHP exposure and increased endometriosis likelihood.
... Although there is evidence of persistent environmental DEHP exposure and its relationship to endometriosis, reports on the molecular mechanisms of DEHP on the pathogenesis of endometriosis are limited. Only 2 studies have shown the effect of in vitro treatment with DEHP on endometrial cells (Kim et al., 2010;Wang et al., 2010). ...
... Only 2 studies have shown the effect of in vitro treatment with DEHP on endometrial cells. DEHP enhanced human endometrial stromal cell viability (Kim et al., 2010), and DEHP stimulated secretion of prostaglandin F2 alpha (PGF2) and inhibited secretion of PGE2 in bovine endometrial cells (Wang et al., 2010). NF-κB is an important transcriptional regulator involved in diverse cellular processes, and IκB modulates the activity of NF-κB. ...
... After DEHP exposure, detectable amounts of DEHP remain in the plasma and peritoneal fluids and thus may affect the functions of reproductive organs (Cobellis et al., 2003). Furthermore, several studies used DEHP exposure as a method for understanding its molecular actions in vitro (Ghosh et al., 2010;Kim et al., 2010;Oh and Lim, 2010). Second, we only used eutopic endometrial stromal cells in this study. ...
Di-(2-ethylhexyl)-phthalate (DEHP) accumulates in the environment, and its exposure is possibly associated with endocrine-related disease in women of reproductive age. The effects of DEHP on human endometrial cells are unknown. We treated human endometrial stromal cells with 10, 100, and 1000 pmol of DEHP and measured reactive oxygen species (ROS) generation, expression levels of antioxidant enzymes, alteration of MAPK/NF-κB signaling and hormonal receptors. DEHP increased reactive oxygen species (ROS) generation and decreased expression of superoxide dismutase (SOD), glutathione peroxidase (GPX), heme oxygenase (HO), and catalase (CAT). By DEHP exposure, p-ERK/p-p38 and NF-κB mediated transcription was increased. Additionally, DEHP induced estrogen receptor-α (ER-α) expression in a dose-dependent manner. This study show the need for future mechanistic studies of oxidative stress, MAPK/NF-κB signaling, and ER-α as molecular mediators of DEHP-associated endometrial stromal cell alterations, which may be associated with the development of endocrine-related disease such as endometriosis.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... Acute exposure to bis(2-ethylhexyl) phthalate (DEHP) has been shown to increase cell viability, oxidative stress, and invasive capacity, altering the inflammatory response and estrogen signaling in endometrial cells; these dysfunctions are shared by both eutopic and ectopic endometrial cells in endometriosis [39][40][41]. ...
... Kim et al. demonstrated increased viability and resistance to toxic levels of hydrogen peroxide in a study on cell viability carried out on Ishikawa cells treated with DEHP and endometrial stromal cells. This supports the pathological theory that, by exposing endometrial cells to DEHP, their viability can be increased, thus contributing to the development of endometriosis outside the uterus [39]. ...
Endometriosis is a chronic gynecological disease, primarily associated with pelvic pain and infertility, that affects approximately 10% of the women of reproductive age. Estrogen plays a central role in endometriosis, and there is growing evidence that endocrine disruptors, such as phthalates, may contribute to its development. This review aimed to determine whether there is a causal relationship between phthalate exposure and the development of endometriosis, as well as the possible effects of phthalates on fertility, by analyzing epidemiological data. After a literature search with a combination of specific terms on this topic, we found that although there are limitations to the current studies, there is a clear association between phthalate exposure and endometriosis. Phthalates can interfere with the cellular processes of the endometrium; specifically, they can bind to PPAR and ER-α and activate TGF-β, promoting different signaling cascades that regulate the expression of specific target genes. This may lead to inflammation, invasion, cytokine alteration, increased oxidative stress, and impaired cell viability and proliferation, culminating in endometriosis. Nevertheless, future research is important to curb the progression and development of endometriosis, and strategies for prevention, diagnosis, and treatment are a priority. In this regard, public policies and recommendations to reduce exposure to phthalates and other endocrine disruptors should be promptly implemented.
... To our knowledge, this is the first report demonstrating that DEHP stimulates human EEEC proliferation via TGF-β/Smad signaling activation. Huang et al. [5] have reported that up to 200 µM DEHP does not affect human endometrial cell viability, whereas Kim et al. [32] have showed that DEHP exposure increases the number of human endometrial cells. Therefore, our data revealed a strong stimulatory effect of DEHP on human EEEC proliferation. ...
... Interestingly, we observed that our 3D culture model is more suitable for the growth and functional maintenance of human EEECs in many aspects than 2D monolayer culture; this assertion was demonstrated by the fact that cells grown in 3D culture exhibited augmented survival, proliferation, migration, and gene and protein expression than those grown in 2D culture. In line with the fact that plasma DEHP concentrations in patients with endometriosis range from 1.5 to 6.2 µM [5], our data suggest that our 3D culture model evaluated with 5 µM DEHP, which is a clinically relevant concentration, more favorably reflects biological responses than traditional monolayer models. Hence, unlike 2D cell culture, our 3D human EEEC culture model has great potential in facilitating the understanding of endometriosis etiology and pathobiology as well as developing diagnostic, therapeutic, and preventive strategies for endometriosis. ...
Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack of understanding of its pathogenesis as well as reliable disease models. Recently, epithelial–mesenchymal transition (EMT) has been suggested to have a significant role in endometriosis pathophysiology. In this study, we found that DEHP treatment enhanced proliferation, migration, and inflammatory responses, along with EMT and stemness induction in human endometrial and endometriotic cells. The selective transforming growth factor-β (TGF-β) receptor type 1/2 inhibitor LY2109761 reversed the DEHP-induced cell proliferation and migration enhancement as well as the increased expression of crucial molecules involved in inflammation, EMT, and stemness, indicating that DEHP-triggered phenomena occur via the TGF-β/Smad signaling pathway. Our study clearly defines the role of DEHP in the etiology and pathophysiological mechanisms of endometriosis and establishes an efficient disease model for endometriosis using a biomimetic 3D cell culture technique. Altogether, our data provide novel etiological and mechanistic insights into the role of DEHP in endometriosis pathogenesis, opening avenues for developing novel preventive and therapeutic strategies for endometriosis.
... ThESCs and Ishikawa cells were seeded at a density of 5.5 × 10 3 and 7.2 × 10 3 cells, respectively, per well in a 96-well plate. After overnight incubation, cells were treated with 125, 250, and 500 µM of H 2 O 2 for 2, 4, and 8 h (Kim et al. 2010, Choi et al. 2018, respectively. Post-treatment, cells were given a wash before the addition of 10% (v/v) Alamar blue (Cat. ...
... Next, to investigate whether oxidative stress has an impact on the levels of XRCC4 protein in endometrial cells, stromal (ThESCs) and epithelial (Ishikawa) cells were subjected to in vitro oxidative stress using H 2 O 2 and checked for XRCC4 protein levels. ThESCs were treated with 125, 250, and 500 μM of H 2 O 2 for 2-8 h (Kim et al. 2010, Choi et al. 2018. Morphology of ThESCs treated with 125 μM of H 2 O 2 appeared unaffected, irrespective of the duration of treatment. ...
Recent data suggest that the DNA damage response (DDR) is altered in the eutopic endometrium (EE) of women with endometriosis and this probably ensues in response to higher DNA damage encountered by the EE in endometriosis. DDR operates in a tissue-specific manner and involves different pathways depending on the type of DNA lesions. Among these pathways, the non-homologous end joining (NHEJ) pathway plays a critical role in the repair of double-stranded DNA breaks. The present study was undertaken to explore whether NHEJ is affected in the EE of women with endometriosis. Towards this, we focused on the X-Ray Repair Cross-Complementing 4 (XRCC4) protein, one of the core components of the NHEJ pathway. Endometrial XRCC4 protein levels in the mid-proliferative phase were found significantly (p<0.05) downregulated in women with endometriosis, compared to control women. Investigation of a microarray-based largest dataset in the GEO database (GSE51981) revealed a similar trend at the transcript level in the EE of women with endometriosis, compared to control women. Further in-vitro studies were undertaken to explore the effects of H2O2-induced oxidative stress on DNA damage, as assessed by γ-H2AFX and 8-hydroxy-2’-deoxyguanosine (8-OHdG) immunolocalization, and XRCC4 protein levels in endometrial stromal (ThESCs) and epithelial (Ishikawa) cells. A significant decrease in XRCC4 protein levels and significantly higher localization of γ-H2AFX and 8-OHdG were evident in ThESCs and Ishikawa cells experiencing oxidative stress. Overall, the study demonstrates that the endometrial XRCC4 expression is dysregulated in women with endometriosis and this could be due to higher oxidative stress in endometriosis.
... Growing evidence implicates phthalate exposure in both the development of endometriosis and its severity [19]. In vitro studies have demonstrated that DEHP promotes endometrial cell viability [63] and endometrial tissue growth outside of the uterine cavity [58]. Specifically, endometrial cells treated in vitro with DEHP exhibit cellular invasiveness and the activation of molecular pathways involved in the establishment of endometriosis and endometrial proliferation (MMP-2 and -9 activation, Erk phosphorylation, and p21-activated kinase expression) [58]. ...
... The p-value for heterogeneity (P-het) of SMDs and I 2 value are shown J Assist Reprod Genet decreases the expression of antioxidant factors such as superoxide dismutase and glutathione peroxidase [64]. Furthermore, phthalates exert a positive, dose-dependent effect on estrogen receptor expression [63]. The action of phthalates on estrogen receptors may also play a role in the development of the estrogen-sensitive tumors such as breast and ovarian cancers [65,66]. ...
Purpose
Endometriosis is a chronic debilitating inflammatory pathology which interests females in their reproductive age. Its pathogenesis has not yet been clearly defined. Recent evidence linked chemical agents as endocrine-disrupting chemicals to endometriosis. Phthalates are a widely used class of such compounds. This study aimed to summarize the current literature evaluating the link between exposure to phthalates and occurrence of endometriosis.
Methods
A systematic review of literature and meta-analysis has been carried out following PRISMA guidelines to assess such link. Fourteen studies have been included in the review. Risk of bias has been assessed through the Newcastle Ottawa Scale.
Results
We observed association between endometriosis and increased urinary levels of MBP/MnBP, MEOHP, and MEHHP, but not for others. Blood-derived analysis showed statistically significant link between endometriosis and BBP, DEHP, DnBP, and MEHP.
Conclusion
Given the wide heterogeneity of included studies, results should be taken with caution. Further studies with more rigorous methodology are encouraged to unravel the true link between this class of toxic compounds and manifestation of endometriosis.
... Even more, the concentration of mono-2-ethylhexyl phthalate (MEHP) was negatively related to the risk of endometriosis [10]. From the aspect of laboratory studies, DEHP exposure was found to enhance the viability of human endometrial cells [13]. To our knowledge, further understanding about the molecular toxicology remains unclear. ...
... Kim et al. found that DEHP exposure at doses of 0.01 and 1 µM led to a significant increase of the viability of human endometrial cells [13]. In contrast, DEHP at 10 ng/mL (about 0.025 µM) did not affect the viability of endometrial cells from cows [25]. ...
Epidemiological studies have shown the possible link between phthalates and endometrium-related gynecological diseases, however the molecular mechanism(s) behind this is/are still unclear. In the study, both primary cultured endometrial cells and an endometrial adenocarcinoma cell line (Ishikawa) were recruited to investigate the effects of di-(2-ethylhexyl) phthalate (DEHP) at human-relevant concentrations. The results showed that DEHP did not affect the viability of either type of cell, which showed different responses to inflammation. Primary cultured cells showed stronger inflammatory reactions than the Ishikawa cell line. The expression of inflammatory factors was induced both at the mRNA and protein levels, however the inflammation did not induce the progress of epithelial-mesenchymal transition (EMT) as the protein levels of EMT markers were not affected after exposure to either cell type. Further study showed that the mRNA levels of peroxisome proliferator-activated receptor gamma (PPARγ) wereup-regulated after exposure. In all, our study showed that human-relevant concentrations of DEHP could elicit the inflammatory response in primary cultured endometrial cells rather than in Ishikawa cell line. PPARγ may act as the mediating receptor in the inflammation reaction.
... Con respeto a los ftalatos, no solo se ha asociado la exposición a los mismos con la presencia de endometriosis, sino que existen pruebas claras del efecto de un ftalato (DEHP) en el crecimiento de las células del endometrio (Kim et al. 2010). Los ftalatos están presentes en champús, acondicionadores, desodorantes, fijadores del pelo, perfumes, jabones, esmalte de uñas, envases de alimentos, recubrimiento de productos farmacéuticos, entre otros. ...
El ensayo titulado “Endometriosis, una lucha ecofeminista desconocida”. La motivación para realizar esta investigación fue solventar las dudas que tenían mis compañeras de la Asociación Estatal de Afectadas de Endometriosis. La endometriosis es una enfermedad femenina asociada a la exposición a tóxicos ambientales presentes en la comida, los cosméticos y textiles. Por eso, muchas afectadas de esta enfermedad se preguntan si realizar cambios en su estilo de vida incidiría en la mejora de su salud. Las lecturas y entrevistas permitieron dilucidar la cuestión y esbozar una agenda ambiental para que las afectadas de enometriosis podamos vindicarla ante las instituciones pertinentes.
... Moreover, phthalates have a favorable, dosedependent influence on the expression of estrogen receptors (ERs) [19]. The activity of phthalates on ERs can also contribute to the development of estrogendependent malignancies, including ovarian and breast cancers [20]. ...
BACKGROUND: Phthalates are compounds found in medical supplies, cellophane wraps, beverage containers, metal can linings, and other products. They have the potential to be significant endocrine disruptors. In experimental animals, thereby affecting their reproductive capacity. Endometriosis is a gynecological condition defined by ectopic endometrial glands and stromal development. Exposure to phthalates has been linked to the development of endometriosis in numerous studies. The dangers of phthalates to women’s reproductive health and fertility have been widely reported. AIM: So far, the relationship between phthalates and infertility is not proven so we decided to see if there was a link between the urine phthalate metabolite levels and endometriosis or idiopathic infertility in Egyptian women. METHODS: Our research was carried out at the infertility outpatient clinic of the Faculty of Medicine of Cairo University. It included 100 female subjects aged 18−40-years-old. Group A (idiopathic infertility; n = 40), Group B (endometriosis; n = 40), and Group C (control; n = 20) were the three age-matched groups that were studied. Using high-performance liquid chromatography (HPLC), the urine levels of mono-2-ethylhexyl phthalate (MEHP) were quantified. RESULTS: The comparison between the study groups has revealed statistically significant differences regarding the urine MEHP levels between Groups A and B. An analysis of the urine MEHP levels in the study Groups A and B has also revealed that the significantly higher urinary MEHP levels are correlated with the use of dietary plastic containers, the use of cosmetics, and the patients’ estrogen levels. Moreover, the urinary MEHP levels of Group A were associated with a history of abortions. CONCLUSIONS: Higher levels of urinary MEHP are positively associated with female reproductive disorders, specifically endometriosis, idiopathic infertility, and abortion.
... Public and scientific concern is being focused to inquire the role of phthalate exposure in estrogen related disease such as endometriosis. Studies have shown accumulation of these substances in blood, follicular fluid, urine, saliva and sweat of infertile females 15,16,17 18,19 , while others reported contradictions 20,21 . Pakistan is a country where plastic and plastic related products are very heavily used, particularly by the lower middle class and modest communities. ...
Background: Endometriosis has a complex multifactorial pathophysiology and is a leading cause of female infertility. Emerging evidence suggests the role of endocrine disrupting chemicals and environmental factors such as Diethyl phthalate (DEP) in the pathophysiology of the disease. Aim: To investigate the serum DEP levels in females with infertility having endometriosis and normal healthy counter parts. Methods: Married females (n=50) age 20-40 years, diagnosed with endometriosis and having history of >1 year of infertility, were selected as cases. Age matched women (n=50) with proven fertility and screened negative for endometriosis were included as controls. Females on any medicine, having co morbid conditions were also excluded from the study. DEP concentration in serum was determined by using High performance liquid chromatography (HPLC). Results: Significantly higher levels (p=0.003) of DEP were seen in endometriosis females (3.76± 1.28 ng/ml) as compared to controls (2.61± 1.72 ng/ml). The comparison of DEP levels between different stages of endometriosis revealed an increasing, but no significant trend with advancement of the disease. Conclusion: High serum DEP levels in patients substantiate their role in disease pathophysiology. Therefore, it may be advisable to pay attention while using such compounds. There is an increased need to regulate the levels of such industrial compounds manufactured for daily use of human beings by efficient and judicious quality assurance plastics and by using the standards set by WHO and/or FDA. Keywords: Phthalate, Endometriosis, Diethyl phthalate, plasticizers, Infertility
... Moreover, women previously diagnosed with endometriosis have an increased risk of developing endometrial cancer, consistent with a link between endometriosis and endometrial cancer [50]. DEHP increases the viability of endometrial cancer cells, and of endometrial stromal cells (ESCs), and the levels of inflammatory mediators such as TNF (tumor necrosis factor)-a in those cells [21,51]. The volume of ectopic endometrial lesions in the endometriosis animal model was significantly increased by DEHP (500, 1000 mg/kg) compared to control [12]. ...
Background
Di-(2-ethylhexyl) phthalate (DEHP) is the most common endocrine disrupting chemical used as a plasticizer. DEHP is associated with the development of endometrium-related diseases through the induction of inflammation. The major therapeutic approaches against endometrial cancer and endometriosis involve the suppression of inflammatory response. Korean red ginseng (KRG) is a natural product with anti-inflammatory and anti-carcinogenic properties. Thus, the purpose of this study is to investigate the effects of KRG on DEHP-induced inflammatory response in endometrial cancer Ishikawa cells and a mouse model of endometriosis.
Methods
RNA-sequencing was performed and analyzed on DEHP-treated Ishikawa cells in the presence and absence of KRG. The effects of KRG on DEHP-induced cyclooxygenase-2 (COX-2) mRNA levels in Ishikawa cells were determined by RT-qPCR. Furthermore, the effects of KRG on the extracellular signal-regulated kinases (ERKs) pathway, COX-2, and nuclear factor-kappa B (NF-κB) p65 after DEHP treatment of Ishikawa cells were evaluated by western blotting. In the mouse model, the severity of endometriosis induced by DEHP and changes in immunohistochemistry were used to assess the protective effect of KRG.
Results
According to the RNA-sequencing data, DEHP-induced inflammatory response-related gene expression was downregulated by KRG. Moreover, KRG significantly inhibited DEHP-induced ERK1/2/NF-κB/COX-2 levels in Ishikawa cells. In the mouse model, KRG administration significantly inhibited ectopic endometriosis growth after DEHP-induced endometriosis.
Conclusions
Overall, these results suggest that KRG may be a promising lead for the treatment of endometrial cancer and endometriosis via suppression of the inflammatory response.
... The first report of the effects of phthalate on endometrial cells showed that DEHP and MEHP stimulated the secretion of prostaglandin F2-α (PGF2-α) and inhibited the secretion of prostaglandin E2 (PGE2). 103 Kim et al. 104 108 In chronic, low-dose DEHP feeding mice, the endometrial stromal cells were significantly increased and changed the localization of steroid hormone receptors. 109 These studies are illustrated in Figure 3. ...
Background
Endometriosis is a common gynecological condition in which stromal or glandular epithelium is implanted in extrauterine locations. Endometriosis causes detrimental effects on the granulosa cells, and phthalate interferes with the biological and reproductive function of endometrial cells at a molecular level.
Methods
This article retrospectively reviewed the studies on phthalate exposure and its relationship with endometriosis. A literature search was performed for scientific articles using the keywords “phthalate and endometriosis,” “endometriosis and granulosa cells,” “phthalate and granulosa cells,” and “phthalates and endometrial cells.”
Results
Endometriosis can affect cytokine production, steroidogenesis, cell cycle progression, expression of estrogen receptor‐α (ER‐α)/progesterone receptor (PR), and cause endoplasmic reticulum stress, senescence, apoptosis, autophagy, and oxidative stress in the granulosa cells. Mono‐n‐butyl phthalate (MnBP) alters the expression of cytokines, cell cycle‐associated genes, ovarian stimulation, steroidogenesis, and progesterone production. Several in vitro studies have demonstrated that phthalate caused inflammation, invasion, change in cytokines, increased oxidative stress, viability, resistance to hydrogen peroxide, and proliferation of endometrial cells.
Conclusion
This might provide new insights about the impact of phthalate on the pathogenesis of endometriosis and its consequences on the ovarian function.
... Vol. 63, No. 1, 2020 Some in vitro studies suggested that exposure to phthalates might play a role in the establishment of endometriosis. In particular, DEHP promotes the viability of ESCs [46], and treatment of endometrial cells with DEHP leads to significant increases in MMP-2 and MMP-9 activities, cellular invasiveness, extracellular signal-regulated kinase (ERK) phosphorylation, and p21-activated kinase 4 expression [47]. In human ESCs, DEHP exposure increases p-ERK/p-p38-and nuclear factor-κB-mediated transcription through an oxidative stress pathway. ...
Nonpersistent endocrine disrupting chemicals (npEDCs) are exogenous chemicals or mixtures of industrial agents that can interfere with the normal action of hormone with a shorter half-life and lower liposolubility. These are commonly found in plastics, medical equipment, detergents, and cosmetics. Recently, role of npEDCs on the changes of ovary and/or uterus development and alterations in hormonal signaling has been emphasized. However, many controversial results exist on the effects of npEDCs and reproductive health of women. Thus, we have focused to review the scientific evidence of a causal relationship between exposure to npEDCs and representative female reproductive issues such as menstrual cycle, endometriosis, uterine fibroids, polycystic ovarian syndrome and infertility/subfertility. Though not all studies indicated a positive correlation of npEDCs with female reproductive issues, the reviewed data illustrated that the majority of the available data strengthen the evidence of reproductive health-related actions of npEDCs. In future, recommendations should be made in order to reduce human exposure to npEDCs and to protect from steadily increasing reproductive health risks.
... Because endometriosis is a common chronic gynaecological disorder associated with pelvic pain and infertility [13], it was important to explore the relationship between PAEs and endometriosis. Although, recent studies have shown that PAEs may have a certain influence on the development of endometriosis [14][15][16][17][18][19], there are also studies that disagree or suggest a lack of consistency in their results [20,21]. In addition, there are a wide variety of PAE metabolites, and their relationship with endometriosis is inconsistent [20,22,23]. ...
Objective: The association between phthalates and endometriosis risk is inconclusive. This meta-analysis aims to evaluate the association between five different phthalate metabolites and endometriosis, based on current evidence. Methods: The literature included PubMed, WOS (web of science), and EMBASE, published until 3 March 2019. We selected the related literature and evaluated the relationship between phthalates exposure and endometriosis risk. All statistical analyses were conducted with STATA version 12.0. Results: Data from eight studies were used in this review. The results of this analysis showed that mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) exposure was potentially associated with endometriosis (OR = 1.246, 95% CI = 1.003–1.549). We have not found positive results in mono(2-ethylhexyl) phthalate (MEHP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) analyses (MEHP: OR = 1.089, 95% CI = 0.858–1.383; MEP: OR = 1.073, 95% CI = 0.899–1.282; MBzP: OR = 0.976, 95% CI = 0.810–1.176; MEOHP: OR = 1.282, 95% CI = 0.874–1.881). In subgroup analyses for regions, the associations were significant between MEHHP and endometriosis in Asia (OR = 1.786, 95% CI = 1.005–3.172, I² = 0%), but not in USA (OR = 1.170, 95% CI = 0.949–1.442, I² = 45.6%). Conclusions: Our findings suggested a potential statistical association between MEHHP exposure and endometriosis, particularly, the exposure of MEHHP might be a potential risk for women with endometriosis in Asia. However, positive associations between the other four Phthalate acid esters (PAEs) and endometriosis was not found. Given the weak strength of the results, well-designed cohort studies, with large sample sizes, should be performed in future.
... Some of the DEHP effects on cells were found in high doses that were not necessarily representative of the human exposure (Zhang et al., 2016;Chen et al., 2013;Kim et al., 2010;Sims et al., 2014). In human breast tissues and milk samples, levels around 13.6 nM and Fig. 2. A four-day exposure to DEHP and MEHP increases cell proliferation of T-47D. ...
The di(2-ethylhexyl) phthalate (DEHP) is a plasticizer incorporated to plastic matrices of widely used consumer products. However, it is gradually released from these products, resulting in a chronic exposure for humans. Although DEHP, similar to other members of the phthalates family, is generally considered as an endocrine disruptor, the mechanisms implicated in its toxicity are yet poorly understood. Our objective was to determine the effects of an exposure to DEHP and to one of its major metabolite, the mono(2-ethylhexyl) phthalate (MEHP) on markers involved in breast carcinogenesis. T-47D cells were exposed to environmentally relevant and higher doses of DEHP and MEHP (0.1–10 000 nM) for 4 days. Our results showed that an exposure to 10 000 nM of DEHP and 0.1 nM of MEHP significantly increased the proliferation of T-47D cells, without inducing apoptosis. In addition, a significant increase in the protein levels of the isoform A of the progesterone receptor (PR) and of nuclear levels of PR were observed in T-47D cells exposed to 10 000 nM of DEHP. Importantly, the increased proliferation and nuclear levels of PR were totally and partially inhibited, respectively, by Mifepristone, a PR antagonist. These results suggest that an exposure to DEHP or MEHP increase cell proliferation by activating PR signaling, which could potentially increase the risks to develop breast cancer. The mechanism of activation of the progesterone pathway by DEHP and the long-term consequences of this activation remained to be elucidated.
... The mechanism triggering the development of endometriosis by phthalates remains unclear. Only Kim et al. (2010) in an in vitro study showed that DEHP (di-(2-ethylhexyl) phthalate) stimulated the stroma of endometrial cells and increased the viability of Ishikawa cells. ...
This review aimed to look into agents and mechanisms characterized as endocrine disrupting chemicals (EDCs). These agents are known to cause several harmful effects to the reproductive system of women and wildlife. There is a wide range of chemicals, developed for commercial use mainly in agriculture, which may cause endocrine disruption. Numerous studies show evidence of environmental contamination. However, no one is being held liable for the damages. The most important potentially harmful agents are identified and described, along with the different effects they have on the female genital area. Brazil is a large consumer of pesticides and others chemicals that may interfere with a normal women's life. We analyzed and described the mode of action and the impacts of different EDCs (bisphenols, phthalates, atrazine, polychlorinated and polybrominated biphenyls, DDT-dichlorodiphenyltrichloroethane; DDE-dichlorodiphenyldichloroethylene; DDD-dichlorodiphenyldichloroethane; and DES-diethylstilbestrol) on the genital area, ovarian steroidogenesis, polycystic ovary syndrome, endometriosis, the structure of the uterus and the vagina, and on the formation of leiomyomas.
... Cobellis et al. showed that the plasma DEHP concentration was associated with endometriosis, suggesting that DEHP plays a potential role in the establishment of endometriosis [59]. DEHP treatment of endometrial cells in vitro has been shown to increase ROS, which indicates that DEHP can induce oxidative stress in human endometrial cells [60] and DEHP-associated endometrial stromal cell alterations may be associated with the progression of the pathogenesis of endometriosis [61]. In vitro exposure to DEHP can lead to the establishment of endometriosis by increasing the invasive and proliferative activities of endometrial cells because DEHP can increase metalloproteinase-(MMP-) 2 and MMP-9 activities and cellular invasiveness. ...
Di-2-ethylhexyl phthalate (DEHP) is extensively used as a plasticizer in many products, especially medical devices, furniture materials, cosmetics, and personal care products. DEHP is noncovalently bound to plastics, and therefore, it will leach out of these products after repeated use, heating, and/or cleaning of the products. Due to the overuse of DEHP in many products, it enters and pollutes the environment through release from industrial settings and plastic waste disposal sites. DEHP can enter the body through inhalation, ingestion, and dermal contact on a daily basis, which has raised some concerns about its safety and its potential effects on human health. The main aim of this review is to give an overview of the endocrine, testicular, ovarian, neural, hepatotoxic, and cardiotoxic effects of DEHP on animal models and humans in vitro and in vivo .
... The average age of menarche of girls in Australia and Europe are three years earlier than before [30][31][32]. Epidemiology found that exposure to phthalates are associated with endometritis, earlier breast development, sexual precocity and earlier onset of puberty [33][34][35][36]. However, the effect of DEHP on pubertal female reproductive system is still not well studied. ...
The pollution of endocrine disruptors and its impact on human reproductive system have attracted much attention. Di-(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, is widely used in food packages, containers, medical supplies and children’s toys. It can cause diseases such as infertility, sexual precocity and uterine bleeding and thus arouse concerns from the society and scholars. The effect of DEHP on pubertal female reproductive system is still not well-studied. This study was to investigate the effects of DEHP on the hypothalamus-uterus in pubertal female rats, reveal the reproductive toxicity of DEHP on pubertal female rats and its mechanism, and provide scientific evidence for the evaluation of toxicity and toxic mechanism of DEHP on reproductive system. Forty-eight pubertal female rats were randomly divided into four groups and respectively administered via oral gavage 0, 250, 500, or 1000 mg/kg/d DEHP in 0.1 mL corn oil/20 g body weight for up to four weeks. Compared with control rats, the DEHP-treated rats showed: (1) higher gonadotropin-releasing hormone (GnRH) level in the hypothalamus, (2) higher protein levels of GnRH in the hypothalamus, and (3) higher mRNA and protein levels of GnRH receptor (GnRHR) in the uterus. Our data reveal that DEHP exposure may lead to a disruption in pubertal female rats and an imbalance of hypothalamus-uterus. Meanwhile, DEHP may, through the GnRH in the hypothalamus and its receptor on the uterus, lead to diseases of the uterus. DEHP may impose a negative influence on the development and functioning of the reproductive system in pubertal female rats.
... 87 Notably, in vitro treatment with DEHP leads to increased viability of endometrial stromal cells. 88 BPA also influences endometrial angiogenesis in vitro. 89 BPA could promote migration and invasion ability of human endometrial carcinoma cells by inducing cyclooxygenase 2 (COX-2) gene expression through the mechanisms involving the MAPK pathway and epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells lose their cell-cell junctions and acquire the mesenchymal phenotype. ...
Civilization, industrialization, and urbanization create an environment where humans are continuously exposed to endocrine disrupting chemicals (EDCs). Some of breast cancers and endometrial cancer, which are the most common female malignant neoplasms, are estrogen-dependent tumors. Prolonged exposure to estrogens or substances with estrogenic properties may be a risk factor for their development. This paper aimed to discuss the potential adverse effect of EDCs on human health, including the role of EDCs in hormone-dependent carcinogenesis. A review of literature regarding the sources of environmental exposure to EDCs and molecular mechanisms of their action was performed. We analyzed the possible mechanisms of how these substances alter the function of the endocrine system, resulting in adverse health effects. Hundreds of substances with endocrine disrupting potential have been identified in our environment. There is accumulating evidence linking exposure to EDCs with the development of mammary and endometrial cancer. By interacting with steroid receptors, EDCs can impact the cellular processes potentially leading to carcinogenesis. There are also data showing the effect of EDCs on immune dysfunction. During lifespan, people are usually exposed to a mixture of various EDCs, which complicates the assessment of individual substances or compounds implicated in cancer development. As the prevalence of hormone-dependent tumors among women continues to increase, their successful prevention is of human benefit. Institutions representing medicine, science, industry, and governments should develop joint strategies to decrease exposure to EDC, and thus to reduce the risk of hormonedependent tumors in women.
... To investigate the mechanism of oestrogen-induced angiogenesis in adenomyosis, we used the endometrial epithelial cells lines ER-positive Ishikawa and ER-negative Ishikawa02 as the model with reference to previous studies [5,[41][42][43][44][45]. First we investigated whether E2 is able to induce VEGF expression in Ishikawa cells. ...
Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial–mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.
... Dibutylphthalte (DBP), butyl benzyl phthalate (BBP), and di(2ethylhexyl)phthalate (DEHP) are typical forms of phthalates. Recent studies report that several phthalates affect the developmental process in animals such as a significant increase in the number of aberrations in chromosome separations in oocytes at anaphase in various aquatic organisms and the alterations in gonadal development and spermatogenesis in amphibians [39][40][41][42] and also cause the developmental problems in human like a shortened anogenital distance among baby boys [43]. In addition, the exposure of phthalates was associated with mental, motor, and behavioral development problem in children and was harmful for formation of genital tract in both male and female [44,45]. ...
Acting as hormone mimics or antagonists in the interaction with hormone receptors, endocrine disrupting chemicals (EDCs) have the potentials of disturbing the endocrine system in sex steroid hormone-controlled organs and tissues. These effects may lead to the disruption of major regulatory mechanisms, the onset of developmental disorders, and carcinogenesis. Especially, among diverse EDCs, xenoestrogens such as bisphenol A, dioxins, and di(2-ethylhexyl)phthalate, have been shown to activate estrogen receptors (ERs) and to modulate cellular functions induced by ERs. Furthermore, they appear to be closely related with carcinogenicity in estrogen-dependant cancers, including breast, ovary, and prostate cancers. In in vivo animal models, prenatal exposure to xenoestrogens changed the development of the mouse reproductive organs and increased the susceptibility to further carcinogenic exposure and tumor occurence in adults. Unlike EDCs, which are chemically synthesized, several phytoestrogens such as genistein and resveratrol showed chemopreventive effects on specific cancers by contending with ER binding and regulating normal ER action in target tissues of mice. These results support the notion that a diet containing high levels of phytoestrogens can have protective effects on estrogen-related diseases. In spite of the diverse evidences of EDCs and phytoestrogens on causation and prevention of estrogen-dependant cancers provided in this article, there are still disputable questions about the dose-response effect of EDCs or chemopreventive potentials of phytoestrogens. As a wide range of EDCs including phytoestrogens have been remarkably increasing in the environment with the rapid growth in our industrial society and more closely affecting human and wildlife, the potential risks of EDCs in endocrine disruption and carcinogenesis are important issues and needed to be verified in detail.
... A study by Durmaz et al. also reported that high plasma levels of DEHP are correlated with pubertal gynecomastia (Durmaz et al., 2010). Third, DEHP has been used in different in vitro systems and has been shown to exert toxic effects on endometrial cells, granulocytes and oocytes (Mlynarcikova et al., 2009; Palleschi et al., 2009; Kim et al., 2010b). ...
Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that has been shown to inhibit growth of mouse antral follicles, however, little is known about the mechanisms by which DEHP does so. Oxidative stress has been linked to follicle growth inhibition as well as phthalate-induced toxicity in non-ovarian tissues. Thus, we hypothesized that DEHP causes oxidative stress and that this leads to inhibition of the growth of antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice (age 31-35days) were cultured with vehicle control (dimethylsulfoxide [DMSO]) or DEHP (1-100μg/ml)±N-acetyl cysteine (NAC, an antioxidant at 0.25-1mM). During culture, follicles were measured daily. At the end of culture, follicles were collected and processed for in vitro reactive oxygen species (ROS) assays to measure the presence of free radicals or for measurement of the expression and activity of various key antioxidant enzymes: Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX) and catalase (CAT). The results indicate that DEHP inhibits the growth of follicles compared to DMSO control and that NAC (0.25-1mM) blocks the ability of DEHP to inhibit follicle growth. Furthermore, DEHP (10μg/ml) significantly increases ROS levels and reduces the expression and activity of SOD1 compared to DMSO controls, whereas NAC (0.5mM) rescues the effects of DEHP on ROS levels and SOD1. However, the expression and activity of GPX and CAT were not affected by DEHP treatment. Collectively, these data suggest that DEHP inhibits follicle growth by inducing production of ROS and by decreasing the expression and activity of SOD1.
Background
Endometriosis has become a global concern. Fifty percent of the affected women become infertile. Ten percent of the female population, which represents women in their reproductive age and girls, is affected globally. It shows a strong correlation with thyroid, endometrial, and breast cancer. It disrupts the psychological, social, and economic wellbeing and sexual life of women.
Main body
Modern hormonal therapy relies upon estrogen–progestin combinations. Other drugs include progestins, gonadotropin-releasing hormone agonists and antagonists. Some patients remain non-responsive to these therapies, and others show adverse effects such as intolerance, weight gain, acne, and seborrhea. Similarly, surgery has its own complications which include late bowel, ureteral perforations, recto-vaginal, and uretero-vaginal fistulas. Neither modern therapeutic nor surgical approaches could alleviate endometriosis. Besides, the cost of treatment is overburdening. This necessitates the designing of an alternative therapeutic approach which could alleviate endometriosis. This has led to the identification of molecular targets and the exploration of different phytoconstituents that could modulate these targets.
Conclusion
Formulation containing different phytoconstituents such as apigenin, genistein, resveratrol, 5α-hydroxycostic acid, hydroxyisocostic acid, anthocyanins, quercetin, naringenin, kaempferol, withaferin-A, ursolic acid, shogaol, curcumin, demethoxycurcumin, capsaicin, ellagic acid, 6‐paradol, 6‐gingerol, carnosic acid, tuberostemonine-O, rosmarinic acid, luteolin, granatin-B, and licochalcone-A may be useful in the treatment of emdometriosis. This formulation may decrease the proliferation of ectopic endometrial stromal cells, their invasion, vascularization, pain sensation, inflammation, gestational diabetes mellitus, and fetal growth restriction. There may be an increase in the fertility rate also. This is due to its ability to regulate the expression of many molecular targets such as VEGF-A/VEGFR2 pathway, p38MAPK/ERK-1/2/PI3K/protein kinase B (AKT), HIF-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-33, TNF-α, NF-kB, IFN-γ, IGF-1-induced activation of IGF-1R, ER-α, and ER-β receptors, miR-95, miR-103, miRNA-138, miRNA-155, miR-183, miR-223, MMP-1, MMP-2, MMP-3, MMP-9, lncRNA-MEG3, lncRNA-H19, Ang-1 mRNA, Ang-2 mRNA, mRNA of urokinase plasminogen activator, mRNA expression and secretion of leptin, CD31, Tie-2, MCP-1 mRNA and protein, HGF, Nrf2, HO1, Keap1, COX-2, PGE-2, MKNK1, and human DNA TOP3A. However, further research is required to determine the safety, compatibility, and therapeutic efficacy of this formulation.
Humans are ubiquitously exposed to environmental endocrine disrupting chemicals such as phthalates. Phthalates can migrate out of products and enter the human body through ingestion, inhalation, or dermal application, can have potential estrogenic/antiestrogenic and/or androgenic/antiandrogenic activity, and are involved in many diseases. As a female reproductive organ that is regulated by hormones such as estrogen, progesterone and androgen, the uterus can develop several disorders such as leiomyoma, endometriosis and abnormal bleeding. In this review, we summarize the hormone-like activities of phthalates, in vitro studies of endometrial cells exposed to phthalates, epigenetic modifications in the uterus induced by phthalate exposure, and associations between phthalate exposure and uterine disorders such as leiomyoma and endometriosis. Moreover, we also discuss the current research gaps in understanding the relationship between phthalate exposure and uterine disorders.
Endometriosis is a hormone-dependent inflammatory gynecological disease of reproductive-age women. It is clinically and pathologically characterized by the presence of functional endometrium as heterogeneous lesions outside the uterine cavity. The two major symptoms are chronic pelvic pain and infertility, which profoundly affect women's reproductive health and quality of life. This significant individual and public health concerns underscore the importance of understanding the pathogenesis of endometriosis. The environmental endocrine-disrupting chemicals (EDCs) are exogenous agents that interfere with the synthesis, secretion, transport, signaling, or metabolism of hormones responsible for homeostasis, reproduction, and developmental processes. Endometriosis has been potentially linked to exposure to EDCs. In this review, based on the robust literature search, we have selected four endocrine disruptors (i) polychlorinated biphenyls (PCB)s (ii) dioxins (TCDD) (iii) bisphenol A (BPA) and its analogs and (iv) phthalates to elucidate their critical role in the etiopathogenesis of endometriosis. The epidemiological and experimental data discussed in this review indicate that these four EDCs activate multiple intracellular signaling pathways associated with proinflammation, estrogen, progesterone, prostaglandins, cell survival, apoptosis, migration, invasion, and growth of endometriosis. The available information strongly indicates that environmental exposure to EDCs such as PCB, dioxins, BPA, and phthalates individually or collectively contribute to the pathophysiology of endometriosis. Further understanding of the molecular mechanisms of how these EDCs establish endometriosis and therapeutic strategies to mitigate the effects of these EDCs in the pathogenesis of endometriosis are timely needed. Moreover, understanding the interactive roles of these EDCs in the pathogenesis of endometriosis will help regulate the exposure to these EDCs in reproductive age women.
Phthalates, as endocrine disrupting chemicals that can alter the endogenous hormones, may be involved in the incidence of endometrial polyp, a benign hormone-dependent condition. We conducted a pilot case-control study from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between phthalate exposures and the risk of endometrial polyp. A total of 40 endometrial polyp patients were matched to 80 controls by age and body mass index in the ratio of 1:2. Two spot urine samples from each subject were quantified for eight phthalate metabolites to enhance exposure assessment. The conditional logistic regression and quantile-based g-computation models were separately used to explore the associations between individual and mixture of urinary phthalate metabolites and the risk of endometrial polyp. After adjusting for covariates, individual chemical analyses showed that urinary monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethylhexyl) phthalate (MEHHP) and the sum of di(2-ethylhexyl) phthalate (ΣDEHP) were associated with increased risks of endometrial polyp, with adjusted odds ratios ranging from 2.62 (95% CI: 0.88, 7.84) for MECPP to 6.96 (95% CI: 1.87, 25.87) for ΣDEHP comparing the extreme exposure categories (all P for trends <0.05 or = 0.057). These associations still persisted when these exposures were modeled as continuous variables. Chemical mixture analyses showed that a simultaneous one-quartile increase in concentrations of eight phthalate metabolites was associated with an elevated odds ratio of 3.14 (95% CI: 1.49, 6.60) in endometrial polyp. Our data suggest that exposure to individual benzylbutyl phthalate (BBzP) and DEHP, as well as mixture of phthalates is associated with increased risk of endometrial polyp. This may inform public health recommendations and policies to avoid phthalate exposures for improving female reproductive health.
Endocrine-disrupting chemicals (EDCs) are exogenous compounds that have been known for their ability to interfere with the action of hormones and affect endocrine pathways, including the ones involved in the development and function of both male and female reproductive systems. EDCs comprise a wide class of compounds, such as pesticides, bisphenol A, phthalates and, parabens, that are present in the environment and in several daily use products. Phthalate esters, compounds commonly used as plasticizers and additives in many industrial applications, have attracted special attention because of the widespread human exposure and the potential for disruption of androgen-dependent development in males. Although phthalates are rapidly metabolized and excreted, their ubiquitous presence ensures continuous exposures throughout different life stages from conception to adult life, as documented by a number of human biomonitoring studies worldwide. Although most research efforts have been placed on the impact of phthalates on male reproductive development and functions, there is a large body of recent experimental and observational data indicating that phthalates can negatively affect female reproductive health, and in particular alter ovarian and uterine functions, potentially contributing to disorders like polycystic ovarian syndrome, endometriosis, and other common female reproductive problems. This review summarizes the most recent experimental and epidemiologic literature on the potential effects of phthalate exposures on female reproductive health and their impact on female fertility.
Recent reports regarding lowering fertility rates in industrialized countries are a cause of concern. In general, social and economic factors are involved, together with a large number of medical conditions (genetic abnormalities, endocrine disorders, malignancies, etc.), hazardous lifestyles (smoking, alcohol consumption, unhealthy eating), and environmental factors. In recent years, researchers have focused their attention on a class of substances now known as endocrine disruptors (EDs), a heterogeneous group of substances that can interfere with endogenous hormones. ED-induced hormonal imbalances may then cause disturbances of many physiological functions (such as puberty, breast development, etc.) and induce several pathologies like cancer (prostate and breast), endocrine and neuroendocrine system dysfunctions, cardiometabolic disorders (obesity, cardiovascular diseases, etc.), and hindrances of reproductive functions in both sexes. Various aspects of reproductive function have been investigated in relation to possible interference of several EDs (phthalate esters, bisphenol A, polychlorinated biphenyls, organophosphate pesticides, perfluoroalkylated compounds, in particular) on several key functions such as gonadal ontogenesis, gonadal steroidogenesis, gonocyte proliferation, pubertal development, and adult fertility. Several EDs have also been associated with the onset of urogenital abnormalities (cryptorchidism, anogenital distance, hypospadia) and reproductive diseases, such as polycystic ovary syndrome and endometriosis. Most of the harmful effects of EDCs were observed in experimental conditions on animals, often after exposure to doses higher than those expected from accidental environmental contact and human studies, but results are relatively scant or controversial. Overall, current evidence does not fully explain the impact of EDs on human male reproductive health. This lack of consistency in experimental and in vivo evidence will definitely require further investigations but, in the meantime, we must prudently point toward a positive association between EDC exposure and reproductive system damage.KeywordsEndocrine disruptorsHuman reproductionInfertilityPhthalateBisphenol APCBOrganophosphate pesticidesPerfluorochemicals
Evidence is growing that phthalate esters play an important role in the pathogenesis of estrogen-dependent gynecologic diseases, especially uterine fibroids. We aimed to investigate whether in vitro treatment with di-(2-ethylhexyl)-phthalate (DEHP) affects angiogenesis, proliferation, and apoptosis in uterine fibroids. To ascertain this, we evaluated vascular endothelial growth factor (VEGF) expression and AKT/ERT phosphorylation and compared the fibroid volume between nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice fed with and without DEHP. VEGF expression was measured using enzyme-linked immunosorbent assay, and AKT/ERK phosphorylation was analyzed by western blot analysis in human myometrial and fibroid cells. The volume of the fibroid tissues implanted to NOD/SCID mice was measured, and the expression of collagen type I protein, Ki-67, proliferating cell nuclear antigen, and B cell lymphoma 2 were analyzed using immunohistochemistry. We could see significant increases in VEGF expression and AKT phosphorylation in human myometrial and fibroid cells treated with DEHP. The volume of the fibroid tissues was significantly increased in NOD/SCID mice fed with DEHP, which was accompanied by increased expression of collagen type I and AKT phosphorylation. Taken together, these results suggest that exposure to phthalate esters may influence uterine fibroid pathogenesis by increasing VEGF and collagen expression and upregulating AKT phosphorylation.
Endometriosis is a common gynecologic disease, worldwide, whose true prevalence is uncertain because it is a difficult disease to diagnose. Endometriosis is a common cause of chronic pelvic pain, dysmenorrhea, and infertility, and is also associated with ovarian cancer. Although the risk factors for endometriosis are unclear, there is increasing evidence that exposure to environmental contaminants, especially phthalates, could affect the pathogenesis of endometriosis. Phthalates are industrial chemicals, used to make flexible plastics, and are present in numerous common plastic products, including medical devices and materials. Several in vitro studies have suggested a positive association between exposure to phthalate, or phthalate metabolites, and the risk of endometriosis. Since the 2000s, studies based on human plasma and urinary concentrations of various phthalate metabolites have been published, but there are still limitations to our understanding of the pathophysiology of phthalates and endometriosis. This report aims to review the current state of knowledge about a possible role of phthalates in the pathogenesis of endometriosis based on cell culture, animal models, and human data.
Endocrine-disrupting chemicals (EDCs) are suspected to be associated with endometriosis (EMs). This study aimed to synthesize published data and evaluate the relationship between four classic EDCs exposure and the risk of EMs. A systematic literature search for original peer reviewed papers was performed in the databases PubMed, EMBASE, and Web of Science based on inclusion criteria up to January 2018. Subsequently, a total of 20 papers conducting 30 studies fulfilled the eligibility criteria and were included in this meta-analysis (four studies for bisphenol A (BPA), 12 studies for polychlorinated biphenyls (PCBs), eight studies for organochlorine pesticides (OCPs), and six studies for phthalate esters (PAEs)). The overall odds ratio (OR) across all exposures and EMs was 1.41 (95% confidence interval (CI): 1.23-1.60). When assessing four specific chemicals, respectively, consistent increases in the risk of EMs were found in PCBs group (OR = 1.58; 95% CI: 1.18-2.12), OCPs group (OR = 1.40; 95% CI: 1.02-1.92) and PAEs group (OR = 1.27; 95% CI: 1.00-1.60), while BPA showed no significant association with EMs. Besides, in the di-(2-ethylhexyl)-phthalate (DEHP) group - the most commonly used PAEs, significant risk was also found (OR = 1.42; 95% CI: 1.19-1.70). The current meta-analysis strengthens the evidence that specific EDCs or their metabolites may promote the occurrence of EMs.
Objective:
To investigate the possible role of phthalate, a ubiquitous chemical used in consumer products, in the pathogenesis of uterine leiomyoma.
Design:
Experimental and prospective case-control study using human samples.
Setting:
University hospital.
Patient(s):
Fifty-three women with histologic evidence of uterine leiomyoma and 33 surgical controls without leiomyoma.
Intervention(s):
Human myometrial and leiomyoma cells were treated with di-(2-thylhexyl)-phthalate (DEHP).
Main outcome measure(s):
Cell viability assay and Western blot analyses after in vitro DEHP treatment; high-performance liquid chromatography electrospray ionization tandem mass spectrometry in cases and controls.
Result(s):
In vitro treatment with DEHP led to an increased viability and increased expressions of proliferating cell nuclear antigen, B-cell lymphoma 2 protein, and type I collagen in myometrial and leiomyoma cells. The urinary concentration of mono-(2-ethyl-5-carboxypentyl) phthalate was higher in women with leiomyoma compared with controls.
Conclusion(s):
These findings suggest that exposure to phthalate may play a role in the pathogenesis of uterine leiomyoma by enhancing proliferative activity, exerting an antiapoptotic effect, and increasing collagen contents in myometrial and leiomyoma cells.
Uterine adenocarcinomas of the endometrium are the eighth leading cause of cancer death in women affecting primarily post menopausal women. While uterine leiomyomas are benign, they are the most common pelvic tumor and are the leading cause for hysterectomy in women. Thus, uterine tumors have a significant impact on women's health. The uterus is exquisitely sensitive to the ovarian steroid hormones estradiol and progesterone and is therefore a target tissue for endocrine disrupting chemicals (EDCs). Such chemicals occur almost ubiquitously in our environment and may have profound effects on normal uterine development and function. This article provides an overview of what is known about the effects of various classes of EDCs on the incidence of uterine tumors in animal models. The importance of choosing the correct animal model, particularly when using rodent models, is discussed. This article also summarizes the different types of uterine tumors that occur in women as well as findings from epidemiological studies that implicate EDCs in uterine tumor development. The development of various human uterine cell lines for in vitro studies has allowed the identification of the mechanisms of action of EDCs and how these chemicals interact with estrogen receptor to act as either estrogen agonists or antagonists. Discussion of the transgenerational effects of exposure to EDCs is also included. While it has been difficult to show a direct link between environmental exposure to EDCs and an increased incidence of uterine tumors in women, the use of in vivo animal models, cell culture systems, and limited epidemiological data suggests a causal relationship between the two. Future studies will undoubtedly lead to an increased understanding of the potential clinical importance of environmental toxicants in the uterus.
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community abouthow environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, andepigeneticchanges, therebyproducingeffects inexposedindividuals as well as theirdescendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in arange that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings canbemuchbetter translated tohumanhealth. Armedwith this information, researchers, physicians, andother healthcare providers can guide regulators and policymakers as they make responsible decisions.
Context:
Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated.
Objective:
We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis.
Design:
For experimental studies, we utilized endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses.
Setting:
The study was conducted at an academic center.
Main outcome measures:
The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk) and expression of p21-activated kinase 4 (Pak4) were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis.
Results:
In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and Pak4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mono (2-ethyl-5-oxohexyl) phthalate (mEOHP), mono (2-ethyl-5-carboxyphentyl) phthalate (mECPP) were significantly higher in women with endometriosis compared with controls.
Conclusion:
These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.
Endocrine disrupting chemicals (EDC) are some chemicals which are acting like hormones inside the body. May kinds of EDCs are acting like estrogen or anti-estrogen, so reproductive systems of male are the main targent organ. EDCs use genetic variations and epigenetic variations as main control route of diseases. When pregnant female is exposed to EDCs, the effects of EDCs on their epigenetic system affect through 3rd generation of offspring. Among many kinds of EDCs, the most notorious EDCs are dioxin and bisphenol A. Phthalates, which have so many kinds and high exposure rate, the effects of phthalate to gynecologic disease were not discovered. So in this paper, we try to summerize the effects of phthalate and new epignetic technique to evalaute the relationship among phthalate and gynecologic disease.
To evaluation of the contribution of DEHP (di-(2-ethylhexyl) phthalate) to the pathophysiology of endometriosis, ECC-1 (human endometrial cancer) cell lines were subjected to DEHP for 48 h with 50 μM DEHP and total RNA was extracted. Quantified spectro-photometrically, and RNA quality was verified via agarose-gel electrophoresis. Gene expression changes were analyzed using oligonucleotide microarray hybridization by comparing the treated and control groups (two-fold change, P<0.05). Three independent samples were analyzed. Data indicated that 522 genes were up-regulated and 379 were down-regulated. These genes were classified according to the GO terms of biological processes and the KEGG pathway. Among biologic processes, regulation of cell death, lipid metabolism, gluconeogenesis, response to hormone stimulus, and regulation of cell differentiation were positively associated with up-regulated genes. Mitosis, meiosis, DNA damage check point, anatomical structure development, reproductive development, and regulation of protein ubiquitination were significantly associated with down-regulated genes. In the KEGG pathway analysis, the MAPK, VEGF, p53, Erbb, mTOR, and phosphatidylinositol signaling pathways were positively associated with up-regulated genes. The cell cycle, oocyte meiosis, spliceosome, and pyrimidine metabolism were positively associated with downregulated genes. In conclusion, After DEHP treatment, some genes associated with cell growth, cell differentiation, meiosis, migration, apoptosis, and the pathophysiology of endometriosis were up regulated.
Endocrine-disrupting chemicals (EDCs) are environmentally persistent exogenous compounds released from various industrial products such as plastics, pesticides, drugs, detergents and cosmetics. They can cause a variety of adverse effects to the reproductive, developmental, immune and nervous systems in humans and wildlife. Di-n-butyl phthalate (DBP) is the main compound of phthalates and is reported to inhibit estrogen receptor (ER)-mediated gene expression and to interfere with normal fetal development of the male reproductive system. Hexabromocyclododecane (HBCD or HBCDD) is one of the brominated flame retardants (BFRs) which have been widely used in plastic, electronic and textile applications and are known to cause endocrine disruption with toxicity of the nervous system. In the present study, the estrogenic effects of DBP and HBCD were examined in an ovarian cancer cell line, BG-1, expressing high levels of ER via MTT assay and semi-quantitative reverse-transcription PCR. Treatment with DBP (10(-8)-10(-5) M) or HBCD (2 x 10(-8) -2 x 10(-6) M) resulted in increased cell proliferation of BG-1 cells as observed with 17-β estradiol (E2). In addition, both DBP and HBCD upregulated the expression levels of cell cycle-regulatory genes, such as cyclin D and cyclin-dependent kinase-4 (cdk-4), which are downstream target genes of ER, at 6 h after treatment. However, the expression of the p21 gene was not altered by DBP or HBCD at any time as with E2. Taken together, these results suggest that DBP and HBCD are EDCs which have apparent estrogenic activities by stimulating the cell proliferation of BG-1 cells and by inducing the expression of cyclin D and cdk-4. Our results suggest that DBP and HBCD have sufficient potency to disrupt the endocrine system and to stimulate cell growth in ER-positive cancer cells.
We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.
P21-activated kinase 1 (Pak1) integrates various signaling pathways that are vital to cell survival and function. This study was performed to evaluate whether sex steroids may regulate the expression of Pak1 in endometrial cells as well as whether its expression is increased in the eutopic endometrium of women with endometriosis.
Following in vitro estradiol (E(2)) and/or medroxyprogesterone acetate (MPA) treatment of Ishikawa cells and endometrial stromal cells (ESCs), Pak1 protein was analyzed utilizing western blot analysis and immunocytochemistry. Immunohistochemistry was performed to evaluate Pak1 immunoreactivity semiquantitatively in women with endometriosis and in controls. To assess the role of Pak1 on endometrial cell viability, crystal violet assay was performed following transfection of Ishikawa cells with Pak1 small interfering RNA (siRNA).
In vitro treatment with E(2) plus MPA or MPA alone led to a significant decrease of Pak1 protein in Ishikawa cells and ESCs (both P < 0.05 versus control). Immunohistochemistry also revealed that Pak1 protein is significantly decreased during the secretory phase in both epithelial and stromal cells in the control subjects (P < 0.001 and P < 0.01, respectively). The immunoreactivity of Pak1 in glandular cells was significantly increased in the eutopic endometrium of women with endometriosis compared with the controls during the secretory phase (P < 0.01). Crystal violet assay has shown that transfection of Ishikawa cells with Pak1 siRNA led to a significant decrease of cellular viability (P < 0.05).
These findings suggest that Pak1 is down-regulated by progesterone during the secretory phase in normal endometrium and increased Pak1 activity during the secretory phase might lead to establishment of endometriosis.
Emerging evidence suggests a potential role for ubiquitous environmental contaminants in the physiopathology of endometriosis. Di-(2-ethylhexyl)-phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride (PVC) formulations, is a widespread environmental contaminant with potentially adverse effects on fertility in animal models. In the present study, we tested the hypothesis that DEHP and/or and its main metabolite, mono-ethylhexyl phthalate (MEHP), play a role in the pathogenesis of endometriosis.
Specimens of blood and peritoneal fluid were collected in a group of women with endometriosis (n = 55), and in age-matched control women (n = 24). Concentrations of DEHP and MEHP were measured in plasma and peritoneal fluid by using high performance liquid chromatography (HPLC). Differences between groups were tested using the Fisher's exact test, Wilcoxon-test, and Kruskal-Wallis analysis of variance.
Endometriotic women showed significantly higher plasma DEHP concentrations than controls (median 0.57 micro g/ml, interquartile range: 0.06-1.23; values range: 0-3.24 versus median 0.18 micro g/ml, interquartile range: 0-0.44; values range: 0-1.03; P = 0.0047) and 92.6% of them had detectable DEHP and /or MEHP in the peritoneal fluid. No significant differences in either the DEHP/MEHP plasma concentrations (P >/= 0.31) or DEHP/MEHP peritoneal fluid concentrations (P >/= 0.66) were observed in the endometriotic patients as a function of the disease stage at the time of diagnosis.
The present findings showed for the first time an association between DEHP plasma concentrations and endometriosis, suggesting a possible role for phthalate esters in the pathogenesis.
The intracellular antioxidant system, based on glutathione (GSH), plays a key role in endometrial detoxification reactions and has been proposed to be involved in the pathogenesis endometriosis. This study was designed to evaluate whether estradiol (E(2)) and proinflammatory cytokines have any effects on expression of glutathione in endometrial stromal cells (ESCs).
Glutathione levels were measured utilizing high-performance liquid chromatography following in vitro culture and treatment of ESCs with estradiol, tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta).
The GSH level in E(2) (10(-8) m) treatment group was significantly higher than in the control group at 48 h (P < 0.05). In vitro treatment of ESCs with TNF-alpha 10 ng/mL as well as E(2) (10(-8) m) plus TNF-alpha 10 ng/mL for 48 hr also led to a significant increase in GSH level (P < 0.05; P < 0.05, respectively). Both IL-1beta 10 ng/mL and E(2) (10(-8) m) plus IL-1beta 10 ng/mL for 48 hr increased GSH level significantly (P < 0.05; P < 0.05, respectively) as well.
These findings might suggest that increased production of estradiol and proinflammatory cytokines in the peritoneal cavity possibly leads to the establishment of endometriosis through increased level of GSH.
In this study, we investigated the regulation of interleukin-8 (IL-8) gene expression in separated endometrial stromal and epithelial cells of human endometrium. This research was conducted as part of an analysis of the role of these cells in regulating the recruitment of leukocytes to the endometrium. Well-characterized model systems were used to study the regulation of endometrial IL-8 gene expression, namely, stromal cells in monolayer culture after first passage and glandular epithelium in primary culture. The levels of IL-8 mRNA and the accumulation of immunoreactive IL-8 in the medium of endometrial stromal cells is culture increased in a time- and concentration-dependent manner upon treatment with IL-1 alpha, tumor necrosis factor-alpha, or serum. The effects of IL-1 alpha plus serum on IL-8 mRNA levels were at least additive. Serum treatment caused a modest stimulation of IL-8 gene transcription (evaluated after 6 h of treatment) in endometrial stromal cells, but serum also acted in these stromal cells to prolong the half-life of IL-8 mRNA by more than 2.5-fold. The regulation of the levels of IL-8 mRNA in endometrial epithelial cells is distinctly different from that in stroma. First, the levels of IL-8 mRNA in non-treated epithelial cells in serum-free medium were much greater than those in stromal cells under similar conditions. Second, whereas the levels of IL-8 mRNA in endometrial epithelial cells also increased in response to serum and to IL-1 in the absence of serum, in the presence of serum, IL-1 treatment caused no appreciable change in the levels of IL-8 mRNA as was the case in endometrial stromal cells.
Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
The objective of this study was to detect the probable association between polychlorinated biphenyls (PCBs) and phthalate esters (PEs), and the occurrence of endometriosis in a prospective case control study. We found that PCBs and PEs may be instrumental in the etiology of endometriosis.
To evaluate the possible association between phthalate esters (PEs) and the occurrence of endometriosis.
Case-control study.
Department of Reproductive Medicine, Bhagawan Mahavir Medical Research Centre, Maternal Health and Reproductive Institute and Department of Analytical R&D, Hetero Research Foundation, Hyderabad, Andhra Pradesh, India.
Blood samples were collected from 49 infertile women with endometriosis (study group); 38 age-matched women without endometriosis (control group I) but with infertility related to tubal defects, fibroids, polycystic ovaries, idiopathic infertility and pelvic inflammatory diseases diagnosed by laparoscopy and a further group of 21 age-matched women (control group II) with proven fertility and no evidence of endometriosis and other gynaecological disorders during laparoscopic sterilisation.
Concentrations of PEs were measured using gas chromatography.
Evaluation of PEs concentrations in women with endometriosis compared with women free from the disease.
Women with endometriosis showed significantly higher concentrations of di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBP), di-n-octyl phthalate (DnOP) and diethyl hexyl phthalate (DEHP) (mean 0.44 [SD 0.41]; 0.66 [SD 0.61]; 3.32 [SD 2.17]; 2.44 [SD 2.17] micrograms/ml) compared with control group I (mean 0.08 [SD 0.14]; 0.12 [SD 0.20]; 0; 0.50 [SD 0.80] micrograms/ml) and control group II (mean 0.15 [SD 0.21]; 0.11 [SD 0.22]; 0; 0.45 [SD 0.68] micrograms/ml). The correlation between the concentrations of PEs and different severity of endometriosis was strong and statistically significant at P < 0.05 for all four compounds (DnBP: r=+0.73, P < 0.0001; BBP: r=+0.78, P < 0.0001; DnOP: r=+0.57, P < 0.0001 and DEHP: r=+0.44, P < 0.0014).
This study suggests that PEs may have an aetiological association with endometriosis.
In regulatory toxicology, the experimental assessment of reproductive toxicity is one of the most costly endpoints to perform. Categorizing chemicals is an approach that can be used to reduce animal tests in risk assessments of chemicals, for example, via REACH (Registration, Evaluation, and Authorization of Chemicals). The category approach was tested for reproductive toxicity with a group of 10 ortho-phthalate esters, with different side chain lengths. Three ortho-phthalates were used for testing the category. Phthalates with side-chain lengths C4 to C6 that are commonly known to cause reproductive effects were included, as well as the recently discovered mechanism that indicates antiandrogenic effects. The differences in physicochemical properties, absorption rates, and metabolism between the phthalates investigated could not fully explain the difference in reproductive toxicity. It was concluded that phthalates with the alkyl side-chain length from C4 to C6 produce similar severe reproductive effects in experimental animals. It is expected that phthalates included in the tight boundaries of the proposed category would all show severe reproductive effects, especially the antiandrogenic effects. Further testing might not be needed for phthalates within these boundaries. If necessary, limited testing could focus on the critical endpoints. Detailed mechanistic information is needed on phthalates to apply the categories for regulatory toxicology.
Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies.
Evaluation of high-sensitivity C-reactive protein in comparison with C-reactive protein as biochemical serum markers in women with endometriosis
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