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Endocrine-disrupting chemicals (EDCs) are compounds, either natural or man-made, that interfere with the normal functioning of the endocrine system. There is increasing evidence that exposure to EDCs can have profound adverse effects on reproduction, metabolic disorders, neurological alterations, and increased risk of hormone-dependent cancer. Stem cells (SCs) are integral to these pathological processes, and it is therefore crucial to understand how EDCs may influence SC functionality. This review examines the literature on different types of EDCs and their effects on various types of SCs, including embryonic, adult, and cancer SCs. Possible molecular mechanisms through which EDCs may influence the phenotype of SCs are also evaluated. Finally, the possible implications of these effects on human health are discussed. The available literature demonstrates that EDCs can influence the biology of SCs in a variety of ways, including by altering hormonal pathways, DNA damage, epigenetic changes, reactive oxygen species production and alterations in the gene expression patterns. These disruptions may lead to a variety of cell fates and diseases later in adulthood including increased risk of endocrine disorders, obesity, infertility, reproductive abnormalities, and cancer. Therefore, the review emphasizes the importance of raising broader awareness regarding the intricate impact of EDCs on human health.

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Diethyl phthalate (DEP), bisphenol A (BPA), and external estradiol 17ß-estradiol (E2) all are endocrine disrupting chemicals (EDCs). Our previous study has found that the development of ceratohyal cartilage (CH) in embryos could be disrupted when the maternal generation was exposed with 8.06 µM DEP, 2.86 µM BPA, and 1.11 µM E2. However, it is still unknown how doses of the residual EDCs in eggs cause abnormal CH development in their offspring. Microinjection is used at the 2-cell stage of embryos to mimic the maternal effect and to observe the toxicities of EDCs in embryos. Results shown that the amounts of DEP, BPA, and E2 were 1.3 × 10-6 ng, 4.7 × 10-7 ng, and 1.4 × 10-7 ng, respectively, inducing the CH angles to become bigger than the control. However, related genes to the migratory pathways of neural crest cells (NCCs) were not influenced upon BPA and E2 treatments. Both sox10 and smad3 gene expressions were up-regulated upon DEP treatment. On the other hand, the CH angles were smaller than the control upon 1.3 × 10-5, 9.4 × 10-6, and 1.4 × 10-6 ng of DEP, BPA, and E2 microinjection, respectively. Furthermore, genes related to migratory NCCs were significantly influenced upon 10-5 ng of BPA, and 10-4 ng of DEP treatments on embryos. According to the data, we suggested that 10-5-10-7 ng of EDCs in eggs could disrupt CH development as well as significantly increase the mortality on their embryos. The present study raises concern that the responses were highly sensitive in embryos through maternal effects.

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Glial cells play a significant role in maintaining brain homeostasis and normal brain development, and their functions can be impaired by exposure to endocrine disruptors. 4-n-Nonylphenol (NP), a representative endocrine disruptor, is widely used in personal care products and industrial materials. NP accumulates in various organs, including the brain, of living organisms and adversely influences brain health. However, studies on the effects of NP on glial cells are limited. This study aims to investigate the effects of NP on glial cells using primary mixed glial cells and offspring mice exposed to NP during gestation and lactation. In vitro experiments revealed that NP exposure stimulated the astrocytes and microglia proliferation but not oligodendrocytes. NP exposure activated microglia and reduced myelin protein expression in oligodendrocytes. Moreover, maternal NP exposure increased the numbers of microglia and oligodendrocytes in the cerebral cortex of adult offspring. NP exposure caused anxiety- and depressive-like behaviors in adult mice. Collectively, these findings suggest that maternal NP exposure negatively affects the brain development in adult offspring mice.

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This study aimed to investigate the effects of 17α-Methyltestosterone (MT) on hepatic lipid metabolism in Gobiocypris rarus. G. rarus was exposed to varying concentrations of MT (0, 25, 50, and 100 ng/L) for durations of 7, 14, and 21 d. Biochemical and transcriptomic analyses were conducted using methods, such as ELISA, RT-qPCR, Western Blotting, and RNA-seq, to decipher the key signals and molecular mechanisms triggered by MT in vivo. The results revealed that MT induced hepatomegaly in G. rarus and markedly increased the hepatic steatosis index (HSI). After 14 d of exposure, significant increase in PPARγ mRNA expression was observed, whereas after 21 d, PPARα mRNA expression was significantly reduced. The expression pattern of SREBP1C mRNA initially decreased before increasing, mirroring the trend observed for SREBP1C protein expression. Furthermore, MT increased the levels of key lipid synthesis enzymes, including HSL, CPT1, GPAT, and FAS, thereby fostering lipid accumulation. RNA-seq analysis revealed that MT modulated hepatic bile acid metabolism via the PPAR pathway, consequently influencing cholesterol and lipid metabolism. Considering the differential metabolic pathways of MT across genders, it is postulated that MT may undergo aromatization to estrogen within G. rarus, thereby exerting estrogenic effects. These findings provide crucial experimental insights into the detrimental effects of MT in aquatic settings, underscoring its implications for safeguarding aquatic organisms and human health.

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This study investigated geospatial distributions of endocrine-disrupting chemicals (EDCs) in the waters of the Dongjiang River and their associations with anthropogenic activities. Fifteen EDCs, with total concentrations in the river water of 149 to 2525 ng/L were detected, with bisphenol-A, 4-nonylphenol, 4-tert-octylphenol, p-hydroxybenzoic acid, and methylparaben being the five predominant EDCs. The total estrogen concentration was high downstream and significantly correlated with the spatial distribution of urban land use, wastewater discharge, population, and gross domestic product, indicating human activities have increased estrogen levels and threatened ecological health. The total risk quotient indicated a high ecological risk of estrogens to fish and a moderate to high ecological risk of personal care products to algae. Estrone, triclosan, bisphenol-A, 4-nonylphenol, and 4-tert-octylphenol were categorized as priority pollutants, which required special concern. Triclosan and triclocarban can serve as reliable chemical indicators for predicting EDC levels based on correlation analysis. The crucial factors affecting EDC levels were identified through the Mantel test and predictor importance was quantified using a multiple regression model, which can help predict occurrences and geospatial distributions of EDCs. Total phosphorus and electrical conductivity were the major predictors of EDC levels, providing promising indicators for monitoring EDCs in river water. Urban land proportion significantly affected phenolic environmental estrogens, natural estrogens, and disinfectants. In the main stream, urban population, urbanization rate, and gross domestic product influenced phenolic environmental estrogen levels. A mini-review of the global distribution of EDCs in river water revealed that income and population differences among countries affect their occurrence, suggesting socioeconomic factors should be considered to mitigate EDC pollution.

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New approach methodologies (NAMs) offer information tailored to the intended application while reducing the use of animals. NAMs aim to develop quantitative structure-activity relationship (QSAR) and quantitive-Read-Across structure-activity relationship (q-RASAR) models to predict and categorize the acute toxicity of known and unknown endocrine-disrupting chemicals (EDCs) against zebrafish. EDCs are a diverse group of toxic substances that disrupt the endocrine system of humans and animals. The q-RASAR model was constructed and verified using validation metrics (R2 = 0.886 and Q2 = 0.814) which found to be more reliable model compare to QSAR model. The substructure fingerprint was well-fitted for the classification model and it was validated using 10-fold average accuracy (Q = 86.88%), specificity (Sp = 88.89%), Matthew's correlation curve (MCC = 0.621) and receiver operating characteristics (ROC = 0.828). The dataset of unknown substances revealed that phenolphthalein (Php) exhibited a significant level of toxicity based on q-RASAR model. The docking and simulation study indicated that the computationally derived important features successfully bound to the target zebrafish sex hormone binding globulin (zfSHBG). The experimental LC50 value of 0.790 mg L-1 was very close to the predicted value of 0.763 mg L-1, which provides high confidence to the developed model.

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Bisphenols constitute a diverse group of endocrine-disrupting chemicals (EDCs) that impact hormone activity. Bisphenol F (BPF) is commonly used as a substitute for Bisphenol A (BPA). The disruption of the immune system by EDCs during embryonic brain development has been suggested as a plausible factor to neurodevelopmental disorders. We investigated the neurotoxic effects of perinatal exposure to BPF on offspring mice. Female mice were exposed to BPF through their drinking water on day 0.5 of pregnancy, and this exposure continued until the offspring mice were weaned, throughout the perinatal period. Our findings revealed that exposure to BPF hindered both growth and neurodevelopment in offspring mice, with a more pronounced effect observed in males. Additionally, transcriptomic analysis was conducted on the brains of male offspring mice exposed to high doses of BPF. In summary, our study indicates that perinatal exposure to BPF results in neurodevelopmental impairments in male offspring mice, linked to oxidative stress, inflammatory responses, and immune dysregulation. These findings underscore that BPF may not be a safe substitute for BPA. Thus, there is a pressing need to reevaluate the current regulation of BPF.

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BACKGROUND: To determine the relationship between mixed exposure to three types of endocrine-disrupting chemicals (EDCs), namely phenyl hydroxides, polycyclic aromatic hydrocarbons (PAHs), and phthalates (PAEs), and risk of arthritis. METHODS: Participants were selected from National Health and Nutrition Examination Survey (NHANES). The relationships between the urinary concentrations of phenyl hydroxides, PAHs, and PAEs and the risk of arthritis were analyzed by generalized linear regression model. The mixed exposure to these EDCs and the risk of arthritis was analyzed by weighted quantile sums (WQSs) and Bayesian kernel machine regression (BKMR) model. RESULTS: Our analysis showed that participants with urinary benzophenone-3 and methylparaben concentrations in the highest quartile (Q4) had an increased risk of arthritis compared with those in Q1. For each one-unit increase in the natural logarithm-converted urinary concentrations of 1-hydroxynapthalene and 2-hydroxynapthalene, the risk of arthritis increased by 5% and 8%, respectively. Chemical mixing index coefficients were significantly associated with risk of arthritis in both WQS positive- and negative-constraint models. In the BKMR model, there was a significant positive correlation between mixed exposure and the risk of arthritis. CONCLUSION: Mixed exposure to phenyl hydroxides, PAHs, and PAEs increased the risk of arthritis, with exposure to PAHs being the key factor.

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Sensitively analyzing phenolic endocrine-disrupting chemicals (EDCs) in environmental substrates and aquatic organisms provides a significant challenge. Here, we developed a novel porous hyper-crosslinked ionic polymer bearing cyano groups (CN-HIP) as adsorbent for the highly efficient solid phase extraction (SPE) of phenolic EDCs in water and fish. The CN-HIP gave an excellent adsorption capability for targeted EDCs over a wide pH range, and the adsorption capacity was superior to that of several common commercial SPE adsorbents. The coexistence of electrostatic forces, hydrogen bond, and π-π interactions was confirmed as the main adsorption mechanism. A sensitive quantitative method was established by coupling CN-HIP based SPE method with high-performance liquid chromatography for the simultaneously determining trace bisphenol A, bisphenol F, bisphenol B and 4-tert-butylphenol in fresh water and fish. The method afforded lower detection limits (S/N = 3) (at 0.03-0.10 ng mL-1 for water and 0.8-4.0 ng g-1 for fish), high accuracy (the recovery of spiked sample at 88.0%-112 %) and high precision (the relative standard deviation < 8.5 %). This work provides a feasible method for detecting phenolic EDCs, and also opens a new perspective in developing functionalized cationic adsorbent.

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The emergence of early onset colorectal cancer (EOCRC) is believed to result from the complex interplay between external environmental factors and internal molecular processes. This review investigates the potential association between environmental exposure to chemicals and climate change and the increased incidence of EOCRC, focusing on their effects on gut microbiota (GM) dynamics. The manuscript explores the birth cohort effect, suggesting that individuals born after 1950 may be at higher risk of developing EOCRC due to cumulative environmental exposures. Furthermore, we also reviewed the impact of environmental pollution, including particulate matter and endocrine disrupting chemicals (EDCs), as well as global warming, on GM disturbance. Environmental exposures have the potential to disrupt GM composition and diversity, leading to dysbiosis, chronic inflammation, and oxidative stress, which are known risk factors associated with EOCRC. Particulate matter can enter the gastrointestinal tract, modifying GM composition and promoting the proliferation of pathogenic bacteria while diminishing beneficial bacteria. Similarly, EDCs, can induce GM alterations and inflammation, further increasing the risk of EOCRC. Additionally, global warming can influence GM through shifts in gut environmental conditions, affecting the host's immune response and potentially increasing EOCRC risk. To summarize, environmental exposure to chemicals and climate change since 1950 has been implicated as contributing factors to the rising incidence of EOCRC. Disruptions in gut microbiota homeostasis play a crucial role in mediating these associations. Consequently, there is a pressing need for enhanced environmental policies aimed at minimizing exposure to pollutants, safeguarding public health, and mitigating the burden of EOCRC.

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Currently, many countries and regions worldwide face the challenge of declining population growth due to persistently low rates of female reproduction. Since 2017, China's birth rate has hit historic lows and continued to decline, with the death rate now equaling the birth rate. Concerns have emerged regarding the potential impact of environmental contaminants on reproductive health, including pregnancy loss. Endocrine-disrupting chemicals (EDCs) like phthalate esters (PAEs), bisphenol A (BPA), triclosan (TCS), and perfluoroalkyl substances (PFASs) have raised attention due to their adverse effects on biological systems. While China's 14th Five-Year Plan (2021-2025) for national economic and social development included the treatment of emerging pollutants, including EDCs, there are currently no national appraisal standards or regulatory frameworks for EDCs and their mixtures. Addressing the risk of EDC mixtures is an urgent matter that needs consideration from China's perspective in the near future. In this Perspective, we delve into the link between EDC mixture exposure and pregnancy loss in China. Our focus areas include establishing a comprehensive national plan targeting reproductive-aged women across diverse urban and rural areas, understanding common EDC combinations in women and their surrounding environment, exploring the relationship between EDCs and pregnancy loss via epidemiology, and reconsidering the safety of EDCs, particularly in mixtures and low-dose scenarios. We envision that this study could aid in creating preventive strategies and interventions to alleviate potential risks induced by EDC exposure during pregnancy in China.

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Astrocytes are now recognized as integral components of neural circuits, regulating their maturation, activity and plasticity. Neuroendocrinology has provided fertile ground for revealing the diverse strategies used by astrocytes to regulate the physiological and behavioural outcomes of neural circuit activity in response to internal and environmental inputs. However, the development of astrocytes in the hypothalamus has received much less attention than in other brain regions such as the cerebral cortex and spinal cord. In this review, we synthesize our current knowledge of astrogenesis in the hypothalamus across various life stages. A distinctive feature of hypothalamic astrogenesis is that it persists all throughout lifespan, and involves multiple cellular sources corresponding to radial glial cells during early development, followed by tanycytes, parenchymal progenitors and locally dividing astrocytes. Astrogenesis in the hypothalamus is closely coordinated with the maturation of hypothalamic neurons. This coordination is exemplified by recent findings in neurons producing gonadotropin-releasing hormone, which actively shape their astroglial environment during infancy to integrate functionally into their neural network and facilitate sexual maturation, a process vulnerable to endocrine disruption. While hypothalamic astrogenesis shares common principles with other brain regions, it also exhibits specific features in its dynamics and regulation, both at the inter- and intra-regional levels. These unique properties emphasize the importance of further exploration. Additionally, we discuss the experimental strategies used to assess astrogenesis in the hypothalamus and their potential bias and limitations. Understanding the mechanisms of hypothalamic astrogenesis throughout life will be crucial for comprehending the development and function of the hypothalamus under both physiological and pathological conditions.

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A common industrial chemical known as bisphenol A (BPA) has been linked to endocrine disruption and can interfere with hormonal signaling pathways in humans and animals. This comprehensive review aims to explore the detrimental consequences of BPA on reproductive organ performance and apoptosis induction, shedding light on the emerging body of evidence from laboratory animal studies. Historically, most studies investigating the connection between BPA and reproductive tissue function have mainly leaned on laboratory animal models. These studies have provided crucial insights into the harmful effects of BPA on several facets of reproduction. This review consolidates an increasing literature that correlates exposure to BPA in the environment with a negative impact on human health. It also integrates findings from laboratory studies conducted on diverse species, collectively bolstering the mounting evidence that environmental BPA exposure can be detrimental to both humans and animals, particularly to reproductive health. Furthermore, this article explores the fundamental processes by which BPA triggers cell death and apoptosis in testicular cells. By elucidating these mechanisms, this review aids a deeper understanding of the complex interactions between BPA and reproductive tissues.

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BACKGROUND: Endocrine-disrupting chemicals (EDCs) have been linked to adverse health outcomes and prenatal exposure is known to impact infant and child development. However, few studies have assessed early developmental consequences of prenatal exposure to two common phenolic compounds, benzophenone-3 (BP-3) and triclosan (TCS). OBJECTIVE: We evaluated the relationship of prenatal exposure to BP-3 and TCS with infant cognition at 7.5 months via performance on a visual recognition memory (VRM) task. METHODS: Drawing from the Illinois Kids Development Study (IKIDS) cohort, prenatal exposure to BP-3 and TCS was assessed in pools of five urine samples collected from each woman across pregnancy. Cognition was measured in 310 infants using a VRM task assessing information processing speed, attention, and recognition memory through infrared eye-tracking. Generalized linear regression estimated exposure-outcome associations, followed by stratification to investigate modification of associations by infant sex and stimulus set. RESULTS: Sampled mothers were more likely to be white, college educated, and middle or high income relative to the US population. Mean chemical exposures were significantly higher than those of adult women in the NHANES cohort. In models adjusted for income, gestational age at birth, and testing age, prenatal BP-3 exposure was associated with an increase in run duration (average time spent looking at the stimuli before looking away) (ß=0.0011, CI -0.0001:0.0022), indicating slower information processing speed, while TCS was associated with significantly longer time to familiarization (time to accrue a total of 20 seconds of looking time to the stimuli) (ß=0.0686, CI 0.0203:0.1168, p<0.01), indicating poorer attention. Stratum-specific analyses isolated both effects to male infants who viewed the second of two stimulus sets. CONCLUSION: Higher prenatal exposure to triclosan was associated with poorer attention in infancy, while benzophenone-3 may be associated with slower information processing speed, particularly among males.

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Binding with proteins is a critical molecular initiating event through which environmental pollutants exert toxic effects in humans. Previous studies have been limited by the availability of three-dimensional (3D) protein structures and have focused on only a small set of environmental contaminants. Using the highly accurate 3D protein structure predicted by AlphaFold2, this study explored over 60 million interactions obtained through molecular docking between 20,503 human proteins and 1251 potential endocrine-disrupting chemicals. A total of 66,613,773 docking results were obtained, 1.2% of which were considered to be high binding, as their docking scores were lower than -7. Monocyte to macrophage differentiation factor 2 (MMD2) was predicted to interact with the highest number of environmental pollutants (526), with polychlorinated biphenyls and polychlorinated dibenzofurans accounting for a significant proportion. Dimension reduction and clustering analysis revealed distinct protein profiles characterized by high binding affinities for perfluoroalkyl and polyfluoroalkyl substances (PFAS), phthalate-like chemicals, and other pollutants, consistent with their uniquely enriched pathways. Further structural analysis indicated that binding pockets with a high proportion of charged amino acid residues, relatively low α-helix content, and high ß-sheet content were more likely to bind to PFAS than others. This study provides insights into the toxicity pathways of various pollutants impacting human health and offers novel perspectives for the establishment and expansion of adverse outcome pathway-based models.

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Dietary exposure risks of 39 multi-class Endocrine Disrupting Chemicals (EDCs) to the threatened Gangetic dolphins (Platanista gangetica) were investigated in a conservation-priority segment of the Ganga River. Elevated EDCs bioaccumulation was observed across prey fish species, with di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP) significantly contributing to the EDC burden. The concentrations of persistent organochlorines in prey revealed a shift from dioxin-like polychlorinated biphenyls (PCBs) to non-dioxin-like PCBs. The prevalence of regulated p,p' DDT (Dichlorodiphenyltrichloroethane) and γ-HCH (Lindane) residues suggests regional non-compliance with regulatory standards. The concentration of some EDCs is dependent on the habitat, foraging behavior, trophic level and fish growth. The potential drivers of EDCs contamination in catchment includes agriculture, vehicular emissions, poor solid waste management, textile industry, and high tourist influx. Risk quotients (RQs) based on toxicity reference value were generally below 1, while the RQ derived from the reference dose highlighted a high risk to Gangetic dolphins from DEHP, DDT, DnBP, arsenic, PCBs, mercury, and cadmium, emphasizing the need for their prioritization within monitoring programs. The study also proposes a monitoring framework to provide guidance on monitoring and assessment of chemical contamination in Gangetic dolphin and habitats.

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The plasticizer di(2-ethylhexyl) phthalate (DEHP) is known to have endocrine-disrupting properties mediated by its many metabolites that form upon exposure in biological systems. In a previous study, we reported an inverse association between DEHP metabolites in the human ovarian follicular fluid (FF) and the responsiveness of the follicles to controlled ovarian stimulation during in vitro fertilization (IVF) treatments. Here, we explored this association further through molecular analysis of the ovarian FF samples. Ninety-six IVF patients from Swedish (N = 48) and Estonian (N = 48) infertility clinics were selected from the previous cohort (N = 333) based on the molar sum of DEHP metabolites in their FF samples to arrive at "high" (mean 7.7 ± SD 2.3 nM, N = 48) and "low" (0.8 ± 0.4 nM, N = 48) exposure groups. Extracellular miRNA levels and concentrations of 15 steroid hormones were measured across FF samples. In addition, FF somatic cells, available for the Estonian patients, were used for RNA sequencing. Differential expression (DE) and interactions between miRNA and mRNA networks revealed that the expression levels of genes in the cholesterol biosynthesis and steroidogenesis pathways were significantly decreased in the high compared to the low DEHP group. In addition, the DE miRNAs were predicted to target key enzymes within these pathways (FDR < 0.05). A decreased 17-OH-progesterone to progesterone ratio was observed in the FF of the high DEHP group (p < 0.05). Additionally, the expression levels of genes associated with inflammatory processes were elevated in the FF somatic cells, and a computational cell-type deconvolution analysis suggested an increased immune cell infiltration into the high DEHP follicles (p < 0.05). In conclusion, elevated DEHP levels in FF were associated with a significantly altered follicular milieu within human ovaries, involving a pro-inflammatory environment and reduced cholesterol metabolism, including steroid synthesis. These results contribute to our understanding of the molecular mechanisms of female reprotoxic effects of DEHP.

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BACKGROUND/ OBJECTIVES: Rosacea is a common chronic inflammatory skin disorder. Endocrinedisrupting chemicals (EDC) are toxic substances, that may gain entry through the skin and subsequently interfere with hormonal and immune functions. Bisphenol A (BPA) and pentachlorophenol sodium (PCS) are two of these EDCs, incriminated in the pathogenesis of certain inflammatory skin disorders. We aimed to test the hypothesis that exposure to BPA and PCS might be involved in the pathogenesis of rosacea. METHODS: This prospective cross-sectional study involved 34 patients with rosacea (18F/16 M; mean age 48.5 ± 11 years) and 34 age and sex-matched healthy controls (20 F/14 M; mean age 48.2 ± 10.2 years). Main anthropometric measures, fasting plasma glucose (FPG), insulin, HOMA-IR, lipids, C-reactive protein (CRP), BPA, and PCS levels were quantified and recorded. RESULTS: Serum CRP (9.6 ± 3.4 vs. 3.7 ± 1.6 mg/L, respectively, p0.05 for all). Serum BPA levels were 55.8 ± 14.4 and 51.9 ± 19.2 ng/mL, and PCS levels were 63.3 ± 45.9 ng/mL and 68.6 ± 40.8 ng/mL for patients and healthy controls, respectively. There was no significant difference in BPA and PCS levels between the two groups (p > 0.05 for both). No significant association was found among HOMAIR, CRP, BPA, and PCS levels (p > 0.05 for all). CONCLUSIONS: Although the present study fails to provide presumptive evidence for the role of BPA and PCS in rosacea, the question as to other EDCs might be involved in its etiopathogenesis remains. This hypothesis requires confirmation in large-scale future prospective trials.

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BACKGROUND: Certain endocrine-disrupting chemicals (EDCs) are widespread in consumer products and may alter glucose metabolism. However, the impact of EDC exposures on glucose and insulin regulation during pregnancy is incompletely understood, despite potential adverse consequences for maternal and infant health. We estimated associations between 37 urinary biomarkers of EDCs and glucose-insulin traits among pregnant women. METHODS: Seventeen phthalate or phthalate substitute metabolites, six environmental phenols, four parabens, and ten organophosphate ester metabolites were quantified in mid-pregnancy urine from 298 participants in the Healthy Start Study. Fasting blood glucose, insulin, and hemoglobin A1c were assessed concurrently, and Homeostasis Model Assessment 2-Insulin Resistance (HOMA2-IR) was calculated. Gestational diabetes diagnoses and screening results were obtained from medical records for a subset of participants. We estimated associations between each EDC and outcome separately using linear and robust Poisson regression models and analyzed EDC mixture effects. RESULTS: The EDC mixture was positively associated with glucose, insulin, and HOMA2-IR, although overall associations were attenuated after adjustment for maternal BMI. Two mixture approaches identified di(2-ethylhexyl) phthalate (DEHP) metabolites as top contributors to the mixture's positive associations. In single-pollutant models, DEHP metabolites were positively associated with fasting glucose, fasting insulin, and HOMA2-IR even after adjustment for maternal BMI. For example, each interquartile range increase in log2-transformed mono(2-ethyl-5-oxohexyl) phthalate was associated with 2.4 mg/dL (95% confidence interval (CI): 1.1, 3.6) higher fasting glucose, 11.8% (95%CI: 3.6, 20.5) higher fasting insulin, and 12.3% (95%CI: 4.2, 21.1) higher HOMA2-IR. Few EDCs were associated with hemoglobin A1c or with a combined outcome of impaired glucose tolerance or gestational diabetes. DISCUSSION: Exposures to phthalates and particularly DEHP during pregnancy are associated with altered glucose-insulin regulation. Disruptions in maternal glucose metabolism during pregnancy may contribute to adverse pregnancy outcomes including gestational diabetes and fetal macrosomia, and associated long-term consequences for maternal and child health.

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Concerns regarding man-made organic chemicals pervading our ecosystem and having adverse and detrimental effects upon organisms, including man, have now been studied for several decades. Since the 1970s, some environmental pollutants were identified as having endocrine disrupting affects. These endocrine disrupting chemicals (EDC) were initially shown to have estrogenic or anti-estrogenic properties and some were also shown to bind to a variety of hormone receptors. However, since the 1990s it has also been identified that many of these EDC additionally, have the ability of causing abnormal alterations in Ca2+ signalling pathways (also commonly involved in hormone signalling), leading to exaggerated elevations in cytosolic [Ca2+] levels, that is known to cause activation of a number of cell death pathways. The major emphasis of this review is to present a personal perspective of the evidence for some types of EDC, specifically alkylphenols and brominated flame retardants (BFRs), causing direct effects on Ca2+ transporters (mainly the SERCA Ca2+ ATPases), culminating in acute cytotoxicity and cell death. Evidence is also presented to indicate that this Ca2+ATPase inhibition, which leads to abnormally elevated cytosolic [Ca2+], as well as a decreased luminal ER [Ca2+], which triggers the ER stress response, are both involved in acute cytotoxicity.