Astrogenesis in the hypothalamus: A life-long process contributing to the development and plasticity of neuroendocrine networks.

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 life-long, 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.

Estrogens regulate early embryonic development of the olfactory sensory system via estrogen-responsive glia.

Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.

Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation.

Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis (n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells (n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.

Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Endocrine disruption and male reproductive disorders: unanswered questions.

Maternal exposure to endocrine-disrupting chemicals (EDCs) in human pregnancy is widely considered as an important cause of adverse changes in male reproductive health due to impaired foetal androgen production/action. However, the epidemiological evidence supporting this view is equivocal, except for certain phthalates, notably diethyl hexyl phthalate (DEHP). Maternal phthalate exposure levels associated with adverse reproductive changes in epidemiological studies are several thousand-fold lower than those needed to suppress foetal androgen production in rats, and direct studies using human foetal testis tissue show no effect of high phthalate exposure on androgen production. This conundrum is unexplained and raises fundamental questions. Human DEHP exposure is predominantly via food with highest exposure associated with consumption of a Western style (unhealthy) diet. This diet is also associated with increased exposure to the most common EDCs, whether persistent (chlorinated or fluorinated chemicals) or non-persistent (phthalates, bisphenols) compounds, which are found at highest levels in fatty and processed foods. Consequently, epidemiological studies associating EDC exposure and male reproductive health disorders are confounded by potential dietary effects, and vice versa. A Western diet/lifestyle in young adulthood is also associated with low sperm counts. Disentangling EDC and dietary effects in epidemiological studies is challenging. In pregnancy, a Western diet, EDC exposure, and maternal living in proximity to industrial sites are all associated with impaired foetal growth/development due to placental dysfunction, which predisposes to congenital male reproductive disorders (cryptorchidism, hypospadias). While the latter are considered to reflect impaired foetal androgen production, effects resulting from foetal growth impairment (FGI) are likely indirect. As FGI has numerous life-long health consequences, and is affected by maternal lifestyle, research into the origins of male reproductive disorders should take more account of this. Additionally, potential effects on foetal growth/foetal testis from the increasing use of medications in pregnancy deserves more research attention.

In vitro assessment of potential endocrine disrupting activities of chlorinated paraffins of various chain lengths.

The production of chlorinated paraffins (CPs) has risen in the past two decades due to their versatile industrial applications. Consequently, CPs are now widely detected in human food sources, the environment, and in human matrices such as serum, the placenta and breast milk. This raises concern about prenatal and postnatal exposure. While some studies suggest that certain short-chained CPs (SCCPs) may have endocrine disrupting properties, knowledge about potential endocrine disrupting potential of medium- (MCCP) and long-chained CPs (LCCPs) remains relativity sparse. Here, we used a panel of in vitro assays to investigate seven pure CPs and two technical mixtures of CPs. These varied in chain length and, chlorination degree. The in vitro panel covered androgen, estrogen, and retinoic acid receptor activities, transthyretin displacement, and steroidogenesis. One of the SCCPs inhibited androgen receptor (AR) activity. All SCCPs induced estrogen receptor (ER) activity. Some SCCPs and MCCPs increased 17ß-estradiol levels in the steroidogenesis assay, though not consistently across all substances in these groups. SCCPs exhibited the most pronounced effects in multiple in vitro assays, while the tested LCCPs showed no effects. Based on our results, some CPs can have endocrine disrupting potential in vitro. These findings warrant further examinations to ensure that CPs do not cause issues in intact organisms, including humans.

The association between endocrine disrupting chemicals and nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease worldwide. Epidemiological studies have reported that exposure of the population to environmental endocrine-disrupting chemicals (EDCs) is associated with NAFLD. However, EDCs are of different types, and there are inconsistencies in the relevant evidence and descriptions, which have not been systematically summarized so far. Therefore, this study aimed to determine the association between population exposure to EDCs and NAFLD. Three databases, including PubMed, Web of science, and Embase were searched, and 27 articles were included in this study. Methodological quality, heterogeneity, and publication bias of the included studies were assessed using the Newcastle-Ottawa scale, I2 statistics, Begg's test, and Egger's test. The estimated effect sizes of the included studies were pooled and evaluated using the random-effects model (I2 > 50 %) and the fixed-effects model ( I2 < 50 %). The pooled-estimate effect sizes showed that population exposure to Phthalates (PAEs) (OR = 1.18, 95 % CI:1.03-1.34), cadmium (Cd) (OR = 1.37, 95 % CI:1.09-1.72), and bisphenol A (OR = 1.43, 95 % CI:1.24-1.65) were positively correlated with the risk of NAFLD. Exposure to mercury (OR =1.46, 95 % CI:1.17-1.84) and Cd increased the risk of "elevated alanine aminotransferase". On the contrary, no significant association was identified between perfluoroalkyl substances (OR =0.99, 95 % CI:0.93-1.06) and NAFLD. However, female exposure to perfluorooctanoic acid (OR =1.82, 95 % CI:1.01-3.26) led to a higher risk of NAFLD than male exposure. In conclusion, this study revealed that EDCs were risk factors for NAFLD. Nonetheless, the sensitivity analysis results of some of the meta-analyses were not stable and demonstrated high heterogeneity. The evidence for these associations is limited, and more large-scale population-based studies are required to confirm these findings.

Bioaccumulation and Potential Endocrine Disruption Risk of Legacy and Emerging Organophosphate Esters in Cetaceans from the Northern South China Sea.

Despite the increasing health risks shown by the continuous detection of organophosphate esters (OPEs) in biota in recent years, information on the occurrence and potential risks of OPEs in marine mammals remains limited. This study conducted the first investigation into the body burdens and potential risks of 10 traditional OPEs (tOPEs) and five emerging OPEs (eOPEs) in 10 cetacean species (n = 84) from the northern South China Sea (NSCS) during 2005-2021. All OPEs, except for 2-ethylhexyl diphenyl phosphate (EHDPHP), were detected in these cetaceans, indicating their widespread occurrence in the NSCS. Although the levels of the ∑10tOPEs in humpback dolphins remained stable from 2005 to 2021, the concentrations of the ∑5eOPEs showed a significant increase, suggesting a growing demand for these new-generation OPEs in South China. Dolphins in proximity to urban regions generally exhibited higher OPE concentrations than those from rural areas, mirroring the environmental trends of OPEs occurring in this area. All OPE congeners, except for EHDPHP, in humpback dolphins exhibited a maternal transfer ratio >1, indicating that the dolphin placenta may not be an efficient barrier for OPEs. The observed significant correlations between levels of OPEs and hormones (triiodothyronine, thyroxine, and testosterone) in humpback dolphins indicated that OPE exposures might have endocrine disruption effects on the dolphin population.

New Mechanism for the Apoptosis of Human Neuroblastoma Cells by the Interaction between Fluorene-9-Bisphenol and the G Protein-Coupled Estrogen Receptor 1.

Fluorene-9-bisphenol (BHPF) is an emerging contaminant. Presently, there is no report on its interaction with G protein-coupled estrogen receptor 1 (GPER). By using an integrated toxicity research scenario that combined theoretical study with experimental methods, BHPF was found to inhibit the GPER-mediated effect via direct receptor binding. Molecular dynamics simulations found that Trp2726.48 and Glu2756.51 be the key amino acids of BHPF binding with GPER. Moreover, the calculation indicated that BHPF was a suspected GPER inhibitor, which neither can activate GPER nor is able to form water channels of GPER. The role of two residues was successfully verified by following gene knockout and site-directed mutagenesis assays. Further in vitro assays showed that BHPF could attenuate the increase in intracellular concentration of free Ca2+ induced by G1-activated GPER. Besides, BHPF showed an enhanced cytotoxicity compared with G15, indicating that BHPF might be a more potent GPER inhibitor than G15. In addition, a statistically significant effect on the mRNA level of GPER was observed for BHPF. In brief, the present study proposes that BHPF be a GPER inhibitor, and its GPER molecular recognition mechanism has been revealed, which is of great significance for the health risk and assessment of BHPF.

Trade-off between Endocrine-Disrupting Compound Removal and Water Permeance of the Polyamide Nanofiltration Membrane: Phenomenon and Molecular Insights.

The polyamide (PA) nanofiltration (NF) membrane has the potential to remove endocrine-disrupting compounds (EDCs) from water and wastewater to prevent risks to both the aquatic ecosystem and human health. However, our understanding of the EDC removal-water permeance trade-off by the PA NF membrane is still limited, although the salt selectivity-water permeance trade-off has been well illustrated. This constrains the precise design of a high-performance membrane for removing EDCs. In this study, we manipulated the PA nanostructures of NF membranes by altering piperazine (PIP) monomer concentrations during the interfacial polymerization (IP) process. The upper bound coefficient for EDC selectivity-water permeance was demonstrated to be more than two magnitudes lower than that for salt selectivity-water permeance. Such variations were derived from the different membrane-solute interactions, in which the water/EDC selectivity was determined by the combined effects of steric exclusion and the hydrophobic interaction, while the electrostatic interaction and steric exclusion played crucial roles in water/salt selectivity. We further highlighted the role of the pore number and residual groups during the transport of EDC molecules across the PA membrane via molecular dynamics (MD) simulations. Fewer pores decreased the transport channels, and the existence of residual groups might cause steric hindrance and dynamic disturbance to EDC transport inside the membrane. This study elucidated the trade-off phenomenon and mechanisms between EDC selectivity and water permeance, providing a theoretical reference for the precise design of PA NF membranes for effective removal of EDCs in water reuse.

Endocrine-Disrupting Chemical Exposure Induces Adverse Effects on the Population Dynamics of the Indo-Pacific Humpback Dolphin.

Cetaceans play a pivotal role in maintaining the ecological equilibrium of ocean ecosystems. However, their populations are under global threat from environmental contaminants. Various high levels of endocrine-disrupting chemicals (EDCs) have been detected in cetaceans from the South China Sea, such as the Indo-Pacific humpback dolphins in the Pearl River Estuary (PRE), suggesting potential health risks, while the impacts of endocrine disruptors on the dolphin population remain unclear. This study aims to synthesize the population dynamics of the humpback dolphins in the PRE and their profiles of EDC contaminants from 2005 to 2019, investigating the potential role of EDCs in the population dynamics of humpback dolphins. Our comprehensive analysis indicates a sustained decline in the PRE humpback dolphin population, posing a significant risk of extinction. Variations in sex hormones induced by EDC exposure could potentially impact birth rates, further contributing to the population decline. Anthropogenic activities consistently emerge as the most significant stressor, ranking highest in importance. Conventional EDCs demonstrate more pronounced impacts on the population compared to emerging compounds. Among the conventional pollutants, DDTs take precedence, followed by zinc and chromium. The most impactful emerging EDCs are identified as alkylphenols. Notably, as the profile of EDCs changes, the significance of conventional pollutants may give way to emerging EDCs, presenting a continued challenge to the viability of the humpback dolphin population.

Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro-In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment.

High-throughput in vitro assays combined with in vitro-in vivo extrapolation (IVIVE) leverage in vitro responses to predict the corresponding in vivo exposures and thresholds of concern. The integrated approach is also expected to offer the potential for efficient tools to provide estimates of chemical toxicity to various wildlife species instead of animal testing. However, developing fish physiologically based toxicokinetic (PBTK) models for IVIVE in ecological applications is challenging, especially for plausible estimation of an internal effective dose, such as fish equivalent concentration (FEC). Here, a fish PBTK model linked with the IVIVE approach was established, with parameter optimization of chemical unbound fraction, pH-dependent ionization and hepatic clearance, and integration of temperature effect and growth dilution. The fish PBTK-IVIVE approach provides not only a more precise estimation of tissue-specific concentrations but also a reasonable approximation of FEC targeting the estrogenic potency of endocrine-disrupting chemicals. Both predictions were compared with in vivo data and were accurate for most indissociable/dissociable chemicals. Furthermore, the model can help determine cross-species variability and sensitivity among the five fish species. Using the available IVIVE-derived FEC with target pathways is helpful to develop predicted no-effect concentration for chemicals with similar mode of action and support screening-level ecological risk assessment.

Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol.

4-Nonylphenol (4-NP), a para-substituted phenolic compound with a straight or branched carbon chain, is a ubiquitous environmental pollutant and food contaminant. 4-NP, particularly the branched form, has been identified as an endocrine disruptor (ED) with potent activities on estrogen receptors. Constitutive Androstane Receptor (CAR) is another crucial nuclear receptor that regulates hepatic lipid, glucose, and steroid metabolism and is involved in the ED mechanism of action. An NP mixture has been described as an extremely potent activator of both human and rodent CAR. However, detailed mechanistic aspects of CAR activation by 4-NP are enigmatic, and it is not known if 4-NP can directly interact with the CAR ligand binding domain (LBD). Here, we examined interactions of individual branched (22NP, 33NP, and 353NP) and linear 4-NPs with CAR variants using molecular dynamics (MD) simulations, cellular experiments with various CAR expression constructs, recombinant CAR LBD in a TR-FRET assay, or a differentiated HepaRG hepatocyte cellular model. Our results demonstrate that branched 4-NPs display more stable poses to activate both wild-type CAR1 and CAR3 variant LBDs in MD simulations. Consistently, branched 4-NPs activated CAR3 and CAR1 LBD more efficiently than linear 4-NP. Furthermore, in HepaRG cells, we observed that all 4-NPs upregulated CYP2B6 mRNA, a relevant hallmark for CAR activation. This is the first study to provide detailed insights into the direct interaction between individual 4-NPs and human CAR-LBD, as well as its dominant variant CAR3. The work could contribute to the safer use of individual 4-NPs in many areas of industry.

Beyond the Nucleus: Plastic Chemicals Activate G Protein-Coupled Receptors.

G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors as novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate, as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at adenosine receptor 1 (ADORA1) and melatonin receptor 1 (MTNR1A). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.

Chemicals in menstrual products: A systematic review.

BACKGROUND: From menarche until menopause, the average menstruator will use over 11 000 tampons or sanitary pads. Vaginal and vulvar tissue is highly permeable, and chemicals are absorbed without undergoing first-pass metabolism. OBJECTIVES: To conduct a review of the literature to determine exposure to environmental chemicals in menstrual products. SEARCH STRATEGY: This review identified 15 papers over the past 10 years. SELECTION CRITERIA: Papers that measured chemicals in menstrual products and that measured human biomarkers of chemical exposure were included. Papers had to also be available in English. DATA COLLECTION AND ANALYSIS: Reviewers assessed the articles and data provided. Multiple chemical groups were found. MAIN RESULTS: Phthalates, volatile organic compounds, parabens, environmental phenols, fragrance chemicals, dioxins and dioxin-like compounds were detected in menstrual products. Research gaps were identified, including the lack of studies on newer products such as menstrual underwear and cups/discs. In addition to measuring chemicals in these products, future research should focus on clarifying the exposure per menstrual cycle to these chemicals to understand how menorrhagia and cycle length influence exposure from menstrual products. CONCLUSION: Menstrual products contained measurable levels of a range of endocrine disrupting chemicals including phthalates, phenols and parabens. This reflects a potentially important route of exposure to chemicals that can impact women's reproductive health.

Non-target estrogenic screening of 60 pesticides, six plant protection products, and tomato, grape, and wine samples by planar chromatography combined with the planar yeast estrogen screen bioassay.

For non-target residue analysis of xenoestrogens in food, sophisticated chromatographic-mass spectrometric techniques lack in biological effect detection. Various in vitro assays providing sum values encounter problems when opposing signals are present in a complex sample. Due to physicochemical signal reduction, cytotoxic or antagonistic effect responses, the resulting sum value is falsified. Instead, the demonstrated non-target estrogenic screening with an integrated planar chromatographic separation differentiated opposing signals, detected and prioritized important estrogenic compounds, and directly assigned tentatively the responsible compounds. Sixty pesticides were investigated, ten of which showed estrogenic effects. Exemplarily, half-maximal effective concentrations and 17ß-estradiol equivalents were determined. Estrogenic pesticide responses were confirmed in six tested plant protection products. In food, such as tomato, grape, and wine, several compounds with an estrogenic effect were detected. It showed that rinsing with water was not sufficient to remove selected residues and illustrated that, though not usually performed for tomatoes, peeling would be more appropriate. Though not in the focus, reaction or breakdown products that are estrogenic were detected, underlining the great potential of non-target planar chromatographic bioassay screening for food safety and food control.

Main factors influencing the perceived health risk of endocrine-disrupting chemicals: A systematic literature review.

Endocrine-disrupting chemicals (EDCs) are linked to rising health issues such as infertility, childhood obesity, and asthma. While some research exists on health risk perceptions of EDCs, a comprehensive understanding across different populations and contexts is needed. We performed a systematic literature review, examining 45 articles published between 1985 and 2023, focusing on both the risk perception of EDCs as a whole as well as individual EDCs found in the environment (e.g., pesticides, bisphenol A, and phthalates). We identified four major categories of factors influencing EDC risk perception: sociodemographic factors (with age, gender, race, and education as significant determinants), family-related factors (highlighting increased concerns in households with children), cognitive factors (indicating that increased EDC knowledge generally led to increased risk perception), and psychosocial factors (with trust in institutions, worldviews, and health-related concerns as primary determinants). This review highlights the complex nature of EDC risk perception, shaped by sociodemographic, family, cognitive, and psychosocial factors, essential for policymakers in crafting educational and communication strategies. Future research should expand to cover more EDCs, use representative samples, and explore the influence of psychosocial factors on risk perception more deeply.

EDC mixtures during pregnancy and body fat at 7 years of age in a Swedish cohort, the SELMA study.

BACKGROUND: Some endocrine disrupting chemicals (EDC), are "obesogens" and have been associated with overweight and obesity in children. Daily exposure to different classes of EDCs demands for research with mixtures approach. OBJECTIVES: This study evaluates the association, considering sex-specific effects, between prenatal exposure to EDC mixture and children's body fat at seven years of age. METHODS: A total of 26 EDCs were assessed in prenatal urine and serum samples from first trimester in pregnancy from 737 mother-child pairs participating in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. An indicator for children's "overall body fat" was calculated, using principal component analysis (PCA), based on BMI, percent body fat, waist, and skinfolds measured at seven years of age. Weighted quantile sum (WQS) regression was used to assess associations between EDC mixture and children's body fat. RESULTS: Principal component (PC1) represented 83.6 % of the variance, suitable as indicator for children's "overall body fat", with positive loadings of 0.40-0.42 for each body fat measure. A significant interaction term, WQS*sex, confirmed associations in the opposite direction for boys and girls. Higher prenatal exposure to EDC mixture was borderline significant with more "overall body fat" for boys (Mean ß = 0.20; 95 % CI: -0.13, 0.53) and less for girls (Mean ß = -0.23; 95 % CI: -0.58, 0.13). Also, higher prenatal exposure to EDC mixture was borderline significant with more percent body fat (standardized score) for boys (Mean ß = 0.09; 95 % CI: -0.04, 0.21) and less for girls (Mean ß = -0.10 (-0.26, 0.05). The chemicals of concern included bisphenols, phthalates, PFAS, PAH, and pesticides with different patterns for boys and girls. DISCUSSION: Borderline significant associations were found between prenatal exposure to a mixture of EDCs and children's body fat. The associations in opposite directions suggests that prenatal exposure to EDCs may present sex-specific effects on children's body fat.

Maternal pre-pregnancy BMI influences the associations between bisphenol and phthalate exposures and maternal weight changes and fat accumulation.

BACKGROUND: Bisphenols and phthalates are two classes of endocrine-disrupting chemicals (EDCs) thought to influence weight and adiposity. Limited research has investigated their influence on maternal weight changes, and no prior work has examined maternal fat mass. We examined the associations between exposure to these chemicals during pregnancy and multiple maternal weight and fat mass outcomes. METHODS: This study included a sample of 318 women enrolled in a Canadian prospective pregnancy cohort. Second trimester urinary concentrations of 2 bisphenols and 12 phthalate metabolites were quantified. Self-reported and measured maternal weights and measured skinfold thicknesses were used to calculate gestational weight gain, 3-months and 3- to 5-years postpartum weight retention, late pregnancy fat mass gain, total postpartum fat mass loss, and late postpartum fat mass retention. Adjusted robust regressions examined associations between chemicals and outcomes in the entire study population and sub-groups stratified by pre-pregnancy body mass index (BMI). Bayesian kernel machine regression examined chemical mixture effects. RESULTS: Among women with underweight or normal pre-pregnancy BMIs, MBzP was negatively associated with weight retention at 3- to 5-years postpartum (B = -0.04, 95%CI: -0.07, -0.01). Among women with overweight or obese pre-pregnancy BMIs, MEHP and MMP were positively associated with weight retention at 3-months and 3- to 5-years postpartum, respectively (B's = 0.12 to 0.63, 95%CIs: 0.02, 1.07). DEHP metabolites and MCNP were positively associated with late pregnancy fat mass gain and late postpartum fat mass retention (B's = 0.04 to 0.18, 95%CIs: 0.001, 0.32). Further, the mixture of EDCs was positively associated with late pregnancy fat mass gain. CONCLUSION: In this cohort, pre-pregnancy BMI was a key determinant of the associations between second trimester exposure to bisphenols and phthalates and maternal weight changes and fat accumulation. Investigations of underlying physiological mechanisms, windows of susceptibility, and impacts on maternal and infant health are needed.

Health risks of Bisphenol-A exposure: From Wnt signaling perspective.

Human beings are routinely exposed to chronic and low dose of Bisphenols (BPs) due to their widely pervasiveness in the environment. BPs hold similar chemical structures to 17ß-estradiol (E2) and thyroid hormone, thus posing threats to human health by rendering the endocrine system dysfunctional. Among BPs, Bisphenol-A (BPA) is the best-known and extensively studied endocrine disrupting compound (EDC). BPA possesses multisystem toxicity, including reproductive toxicity, neurotoxicity, hepatoxicity and nephrotoxicity. Particularly, the central nervous system (CNS), especially the developing one, is vulnerable to BPA exposure. This review describes our current knowledge of BPA toxicity and the related molecular mechanisms, with an emphasis on the role of Wnt signaling in the related processes. We also discuss the role of oxidative stress, endocrine signaling and epigenetics in the regulation of Wnt signaling by BPA exposure. In summary, dysfunction of Wnt signaling plays a key role in BPA toxicity and thus can be a potential target to alleviate EDCs induced damage to organisms.