Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age.

Background: In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Methods: Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences -0.07 (95% CI -0.13, -0.02), -0.09 (-0.15, -0.02), -0.08 (95% CI -0.14, -0.02), and -0.08 (-0.13, -0.03) µg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Comparative in silico and in vitro evaluation of possible toxic effects of bisphenol derivatives in HepG2 cells.

Introduction: Bisphenols are widely used in the production of polycarbonate plastics and resin coatings. Bisphenol A (BPA) is suggested to cause a wide range of unwanted effects and "low dose toxicity". With the search for alternative substances to BPA, the use of other bisphenol derivatives namely bisphenol F (BPF) and bisphenol S (BPS) has increased. Methods: In the current study, we aimed to evaluate the in silico predicted inhibitory concentration 50s (pIC50s) of bisphenol derivatives on immune and apoptotic markers and DNA damage on HepG2 cells. Moreover, apoptotic, genotoxic and immunotoxic effects of BPA, BPF and BPS were determined comparatively. Effects of bisphenols on apoptosis were evaluated by detecting different caspase activities. The genotoxic effects of bisphenols were evaluated by measuring the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-oxoguanine glycosylase (OGG1). To determine the immunotoxic effect of bisphenol derivatives, the levels of interleukin 4 (IL-4) and interleukin 10 (IL-10), transforming growth factor beta (TGF-ß) and tumor necrosis factor-alpha (TNF-α), which are known to be expressed by HepG2 cells, were measured. Results: In silico data indicate that all of the bisphenols may cause alterations in immune and apoptotic markers as well as DNA damage at low doses. In vitro data revealed that all bisphenol derivatives could affect immune markers at inhibitory concentration 30s (IC30s). In addition, BPF and BPS may also have apoptotic immunotoxic effects. Conclusion: Both in silico and in vivo research are needed further to examine the toxic effects of alternative bisphenol derivatives.

Disruptive effects of plasticizers bisphenol A, F, and S on steroidogenesis of adrenocortical cells.

Introduction: Endocrine disrupting chemicals (EDCs) are known to interfere with endocrine homeostasis. Their impact on the adrenal cortex and steroidogenesis has not yet been sufficiently elucidated. This applies in particular to the ubiquitously available bisphenols A (BPA), F (BPF), and S (BPS). Methods: NCI-H295R adrenocortical cells were exposed to different concentrations (1nM-1mM) of BPA, BPF, BPS, and an equimolar mixture of them (BPmix). After 72 hours, 15 endogenous steroids were measured using LC-MS/MS. Ratios of substrate and product of CYP-regulated steps were calculated to identify most influenced steps of steroidogenesis. mRNA expression of steroidogenic enzymes was determined by real-time PCR. Results: Cell viability remained unaffected at bisphenol concentrations lower than 250 µM. All tested bisphenols and their combination led to extensive alterations in the quantified steroid levels. The most profound fold changes (FC) in steroid concentrations after exposure to BPA (>10µM) were seen for androstenedione, e.g. a 0.37±0.11-fold decrease at 25µM (p≤0.0001) compared to vehicle-treated controls. For BPF, levels of 17-hydroxyprogesterone were significantly increased by 25µM (FC 2.57±0.49, p≤0.001) and 50µM (FC 2.65±0.61, p≤0.0001). BPS treatment led to a dose-dependent decrease of 11-deoxycorticosterone at >1µM (e.g. FC 0.24±0.14, p≤0.0001 at 10µM). However, when combining all three bisphenols, additive effects were detected: e.g. 11-deoxycortisosterone was decreased at doses >10µM (FC 0.27±0.04, p≤0.0001, at 25µM), whereas 21-deoxycortisol was increased by 2.92±0.20 (p≤0.01) at 10µM, and by 3.21±0.45 (p≤0.001) at 50µM. While every measured androgen (DHEA, DHEAS, androstenedione, testosterone, DHT) was lowered in all experiments, estradiol levels were significantly increased by BPA, BPF, BPS, and BPmix (e.g. FC 3.60±0.54, p≤0.0001 at 100µM BPF). Calculated substrate-product ratios indicated an inhibition of CYP17A1-, and CYP21A2 mediated conversions, whereas CYP11B1 and CYP19A1 showed higher activity in the presence of bisphenols. Based on these findings, most relevant mRNA expression of CYP genes were analysed. mRNA levels of StAR, CYP11B1, and CYP17A1 were significantly increased by BPF, BPS, and BPmix. Discussion: In cell culture, bisphenols interfere with steroidogenesis at non-cytotoxic levels, leading to compound-specific patterns of significantly altered hormone levels. These results justify and call for additional in-vivo studies to evaluate effects of EDCs on adrenal gland functionality.

Development of ternary hybrid composites of transition metal and noble metal-based heterostructures: Ultrasensitive simultaneous electrochemical detection of bisphenol A and bisphenol S in food samples.

Bisphenols threaten human health and sensitive detection is crucial. The present study aims to develop ternary composites of copper metal-organic framework (Cu-MOF) with AuAg microstructures. The composite structure was formed by a galvanic displacement reaction and confirmed using SEM. A binder-free catalyst was used to study the electrochemical redox reaction of bisphenol A (BPA) and bisphenol S (BPS); an irreversible cyclic voltammetric signal at +0.70 V and + 0.91 V (vs. Ag/AgCl), in the dynamic range of 20 nM to 2.0 mM, and 10 nM to 1.0 mM, with limits of detection of 2.9 nM, and 3.2 nM (S/N = 3) was obtained. Practical analysis was applied to frozen tomatoes, tuna fish, milk powder, PET bottles, raw milk, and urine samples with a recovery rate of 94.00-100.80% (n = 3). Voltammetric results were validated using HPLC detection with high precision. The sensor is a promising alternative platform for measuring BPA in food samples.

Maternal bisphenols exposure and thyroid function in children: a systematic review and meta-analysis.

Background: Evidence from animal experiments and epidemiological studies has reported controversial results about the effects of prenatal bisphenols (BPs) exposure on childhood thyroid function. This study aims to explore the associations of prenatal exposure to BPs with thyroid-related hormones (THs) in newborns and early childhood, with a particular focus on the sex-dependent and exposure level effects. Methods: Correlated studies were systematically searched from PubMed, Web of Science, Medline, Cochrane, and Embase until February 21, 2024. The exposures assessed include bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), bisphenol AF (BPAF), and tetrachlorobisphenol A (TCBPA). THs measured were thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), free tri-iothyronine (FT3), and free thyroxine (FT4). Effect estimates were quantified using coefficients from multivariable regression models. Statistical analyses were completed using Stata 16.0. The methodological quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS). Results: Eleven cohort studies comprising 5,363 children were included in our meta-analysis. Prenatal bisphenol concentrations were statistically significant related to alterations in thyroid hormones in children, exclusively in female offspring, including reduced TSH (ß = -0.020, 95% CI: -0.036, -0.005) and increased TT3 levels (ß = 0.011, 95% CI: 0.001, 0.021), and exposure to high concentration of bisphenols (>1.5 ug/g creatinine) significantly reduced FT3 levels in children (ß = -0.011, 95% CI: -0.020, -0.003). Conclusion: Prenatal bisphenol exposure is linked to alterations in thyroid hormone levels in girls, necessitating enhanced measures to control bisphenol exposure levels during pregnancy for child health protection. Systematic Review Registration: https://inplasy.com, identifier INPLASY202450129.

Effect of crosslinker/porogen ratio on sponge-nested polymer monoliths for solid-phase extraction.

Polymer monoliths can be polymerised within different molds, but limited options are available for the preparation of free-standing polymer monoliths for analytical sample preparation, and in particular, solid-phase extraction (SPE). Commercial melamine-formaldehyde sponges can be used as supports for the preparation of polymer monoliths, due its flexibility, giving various shapes to monoliths. Herein, the crosslinker/porogen ratio of highly porous sponge-nested divinylbenzene (DVB) polymer monoliths has been evaluated. Monoliths prepared using different crosslinker/porogen ratios were applied to the extraction of bisphenol F, bisphenol A, bisphenol AF, and bisphenol B. Monoliths containing 50 wt % DVB and 50 wt % porogens presented the highest recovery of bisphenols. Under the optimised conditions, the developed method showed a linear range between 2.5 µg L-1 and 150 µg L-1 for BPA and BPAF, and between 5 µg L-1 and 150 µg L-1 for BPB and BPF. The limits of detection (LOD, S/N = 3) and limits of quantification (LOQ, S/N = 10) ranged from 0.36 µg L-1 to 1.09 µg L-1, and from 1.20 µg L-1 to 3.65 µg L-1, respectively. The recoveries for spiked bisphenols (10 µg L-1) in tap water and water contained in a polycarbonate containers were between 82 % and 114 %.

Combined toxicity of pristine or artificially aged tire wear particles and bisphenols to Tigriopus japonicus.

Tire wear particles (TWPs) are considered an important component of microplastic pollution in the marine environment and occur together with a variety of aquatic pollutants, including frequently detected bisphenols. The adverse effects of TWPs or bisphenols on aquatic organisms have been widely reported. However, the combined toxicity of TWPs and bisphenols is still unknown. In this study, the combined toxicity of both pristine (p-) and aged TWPs (a-TWPs) and four bisphenols ((bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF)) to Tigriopus japonicus was evaluated. TWPs increased the toxicity of BPA and BPF but decreased the toxicity of BPAF. For BPS, there was synergistic toxic effect in the presence of p-TWPs, but slightly antagonistic effect was observed in the presence of a-TWPs. This adsorption of BPAF by TWPs resulted in a reduction of its toxicity to the copepod. A-TWPs could release more Zn than p-TWPs, and the released Zn contributed to the synergistic effect of TWPs and BPA or BPF. The aggregation formed by TWPs in certain sizes (e.g., 90-110 µm) could cause intestinal damage and lipid peroxidation in T. japonicus. The synergistic effect of p-TWPs and BPS might be due to the aggregation size of the binary mixture. The results of the current study will be important to understand the combined toxic effect of TWPs and bisphenols and the potential toxic mechanisms of the binary mixture.

An in vitro model system for testing chemical effects on microbiome-immune interactions - examples with BPX and PFAS mixtures.

Introduction: More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly understood. Manufacturers are required to carry out toxicological studies, for example on the reproductive or nervous systems, before putting a new substance on the market. However, toxicological safety does not exclude effects resulting from chronic exposure to low doses or effects on other potentially affected organ systems. This is the case for the microbiome-immune interaction, which is not yet included in any safety studies. Methods: A high-throughput in vitro model was used to elucidate the potential effects of environmental chemicals and chemical mixtures on microbiome-immune interactions. Therefore, a simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species was cultured in vitro in a bioreactor that partially mimics intestinal conditions. The bacteria were continuously exposed to mixtures of representative and widely distributed environmental chemicals, i.e. bisphenols (BPX) and/or per- and polyfluoroalkyl substances (PFAS) at concentrations of 22 µM and 4 µM, respectively. Furthermore, changes in the immunostimulatory potential of exposed microbes were investigated using a co-culture system with human peripheral blood mononuclear cells (PBMCs). Results: The exposure to BPX, PFAS or their mixture did not influence the community structure and the riboflavin production of SIHUMIx in vitro. However, it altered the potential of the consortium to stimulate human immune cells: in particular, activation of CD8+ MAIT cells was affected by the exposure to BPX- and PFAS mixtures-treated bacteria. Discussion: The present study provides a model to investigate how environmental chemicals can indirectly affect immune cells via exposed microbes. It contributes to the much-needed knowledge on the effects of EDCs on an organ system that has been little explored in this context, especially from the perspective of cumulative exposure.

A Personalized Intervention to Increase Environmental Health Literacy and Readiness to Change in a Northern Nevada Population: Effects of Environmental Chemical Exposure Report-Back.

BACKGROUND: Interventions are needed to help people reduce exposure to harmful chemicals from everyday products and lifestyle habits. Report-back of individual exposures is a potential pathway to increasing environmental health literacy (EHL) and readiness to reduce exposures. OBJECTIVES: Our objective was to determine if report-back of endocrine-disrupting chemicals (EDCs) can reduce EDC exposure, increase EHL, and increase readiness to change (i.e., to implement EDC exposure-reduction behaviors). METHODS: Participants in the Healthy Nevada Project completed EHL and readiness-to-change surveys before (n = 424) and after (n = 174) a report-back intervention. Participants used mail-in kits to measure urinary biomarkers of EDCs. The report-back of results included urinary levels, information about health effects, sources of exposure, and personalized recommendations to reduce exposure. RESULTS: EHL was generally very high at baseline, especially for questions related to the general pollution. For questions related to chemical exposures, responses varied across several demographics. Statistically reliable improvements in EHL responses were seen after report-back. For readiness to change, 72% were already or planning to change their behaviors. Post-intervention, women increased their readiness (p = 0.053), while men decreased (p = 0.007). When asked what challenges they faced in reducing exposure, 79% cited not knowing what to do. This dropped to 35% after report-back. Participants with higher propylparaben were younger (p = 0.03) and women and participants who rated themselves in better health had higher levels of some phthalates (p = 0.02-0.003 and p = 0.001-0.003, respectively). After report-back, monobutyl phthalate decreased among the 48 participants who had valid urine tests before and after the intervention (p < 0.001). CONCLUSIONS: The report-back intervention was successful as evidenced by increased EHL behaviors, increased readiness to change among women, and a decrease in monobutyl phthalate. An EHL questionnaire more sensitive to chemical exposures would help differentiate high and low literacy. Future research will focus on understanding why men decreased their readiness to change and how the intervention can be improved for all participants.

Sex-Specific and Trimester-Specific Associations of Prenatal Exposure to Bisphenols, Parabens, and Triclosan with Neonatal Birth Size and Gestational Age.

Bisphenols, parabens, and triclosan (TCS) are common endocrine disrupters used in various consumer products. These chemicals have been shown to cross the placental barrier and affect intrauterine development of fetuses. In this study, we quantified serum levels of six bisphenols, five parabens, and TCS in 483 pregnant women from southern China. Quantile-based g-computation showed that combined exposure to bisphenols, parabens, and TCS was significantly (p < 0.05) and negatively associated with birth weight (ß = -39.9, 95% CI: -73.8, -6.1), birth length (ß = -0.19, 95% CI: -0.34, -0.04), head circumference (ß = -0.13, 95% CI: -0.24, -0.02), and thoracic circumference (ß = -0.16, 95% CI: -0.29, -0.04). An inverse correlation was also identified between mixture exposure and gestational age (ß = -0.12, 95% CI: -0.24, -0.01). Bisphenol A (BPA), bisphenol Z (BPZ), bisphenol AP (BPAP), propylparaben (PrP), and TCS served as the dominant contributors to the overall effect. In subgroup analyses, male newborns were more susceptible to mixture exposure than females, whereas the exposure-outcome link was prominent among pregnant women in the first and second trimesters. More evidence is warranted to elucidate the impacts of exposure to mixtures on birth outcomes, as well as the underlying mechanisms.

The mediating role of steroid hormones in the relationship between bisphenol A and its alternatives bisphenol S and F exposure and preeclampsia.

Steroid hormone imbalance is believed to increase the odds of developing PE. Bisphenol A (BPA) and its substitutes (e.g., bisphenol S (BPS) and bisphenol F (BPF)) have estrogen-like effects, and its exposure may be related to the development of preeclampsia (PE). To explore the effects of bisphenol exposure on maternal serum steroid hormones and the potential mediating role of steroid hormones in the association between bisphenol exposure and developing PE, concentrations of bisphenols and steroid hormones in serum samples of 383 pregnant women were examined before delivery (including 160 PE cases and 223 control cases). Multivariable logistic and linear models were used to explore the associations of maternal serum bisphenols concentrations with both maternal steroid hormones and PE risk. Mediation modeling was employed to evaluate the mediating role of steroid hormones in the association between bisphenols and PE. Results showed that maternal serum BPS concentrations were positively associated with testosterone (T) concentrations. The mediation analyses suggested that approximately 10.17 % of the associations between BPS concentrations and the development of PE might be mediated by maternal T. In conclusion, maternal exposure to BPS during pregnancy is linked to higher maternal T concentrations, which might increase the odds of developing PE. T might mediate the association between BPS exposure and the development of PE.

[Determination of six bisphenols in human urine by ultra-high performance liquid chromatography-tandem mass spectrometry].

OBJECTIVE: To develop and validate a solid phase extraction-ultra-high performance liquid chromatography-tandem mass spectrometry method for the determination of six bisphenols(bisphenol S, bisphenol F, bisphenol A, 2, 2'-methylenediphenol, bisphenol AF, bisphenol AP) in urine. METHODS: After enzymolysis of urine sample, the target substances were quickly purified and extracted by WAX solid phase extraction column. On ACQUITY BEH C_(18) column(2.1 mm×100 mm, 1.7 µm), the mobile phase of water and methanol was used to separate. Finally, multi-reaction detection was carried out under electrospray negative ion scanning, and quantification was carried out by internal standard method. RESULTS: The correlation coefficients(r) of the target compounds were all more than 0.998 in the range of 0.1-50.0 ng/mL, the linearity was good, and the detection limits were all lower than 0.1 ng/mL. The recoveries of the three standard concentrations(0.5, 5.0 and 50.0 ng/mL) were all between 80% and 120%, and the relative standard deviation was less than 20%(n=5). The standard reference material was detected and the concentration was within the reference range. CONCLUSION: This method can be used to detect six bisphenols in urine quickly and accurately, is suitable for the trace analysis of bisphenol compounds in human urine.

Hollow multi-shelled MOF derivative adsorbent for efficient magnetic solid-phase extraction of several typical endocrine disrupting compounds from water.

Bisphenols and benzophenones are two typical kinds of endocrine-disrupting compounds (EDCs) that have been extensively detected in water environments, posing unanticipated risks to aquatic organisms and humans. It is urgent to develop efficient sample pretreatment methods for precise measurement of such EDCs. In this study, a magnetic and multi-shelled metal-organic framework derivative material has been prepared to extract and enrich trace bisphenols and benzophenones from water. Via a solvothermal reaction induced by sodium citrate followed by a carbonization treatment, a ZIF-67@ZIF-8 derived CoZn-magnetic hierarchical carbon (CoZn-MHC) material has been synthesized as a high-performance magnetic solid-phase extraction (MSPE) adsorbent. This adsorbent exhibited a good specific surface area (213.80 m2⋅g-1) and a saturation magnetization of 63.2 emu·g-1. After the optimization of several parameters (including adsorbent dosage, extraction time, pH, ionic strength, desorption solvent, and solvent volume), an efficient MSPE method for several EDCs (comprising bisphenols and benzophenones) was developed with a good linear range (R2 ≥ 0.990), a high sensitivity range (LODs: 0.793-5.37 ng⋅L-1), and good reusability (RSD ≤4.67 % in five consecutive tests). Furthermore, the material exhibited commendable resistance to matrix interference in natural water samples with the recovery rates of target compounds ranging from 74.8 % to 107 %. We envision that the preparation strategy of this functional metal-organic framework (MOF)-based adsorbent for EDCs may provide insights for relevant research in the future.

Structural Studies on the Binding Mode of Bisphenols to PPARγ.

Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study.

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.

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.

Rapid identification of reproductive toxicants among environmental chemicals using an in vivo evaluation of gametogenesis in budding yeast Saccharomyces cerevisiae.

Infertility affects ∼12 % of couples, with environmental chemical exposure as a potential contributor. Of the chemicals that are actively manufactured, very few are assessed for reproductive health effects. Rodents are commonly used to evaluate reproductive effects, which is both costly and time consuming. Thus, there is a pressing need for rapid methods to test a broader range of chemicals. Here, we developed a strategy to evaluate large numbers of chemicals for reproductive toxicity via a yeast, S. cerevisiae high-throughput assay to assess gametogenesis as a potential new approach method (NAM). By simultaneously assessing chemicals for growth effects, we can distinguish if a chemical affects gametogenesis only, proliferative growth only or both. We identified a well-known mammalian reproductive toxicant, bisphenol A (BPA) and ranked 19 BPA analogs for reproductive harm. By testing mixtures of BPA and its analogs, we found that BPE and 17 ß-estradiol each together with BPA showed synergistic effects that worsened reproductive outcome. We examined an additional 179 environmental chemicals including phthalates, pesticides, quaternary ammonium compounds and per- and polyfluoroalkyl substances and found 57 with reproductive effects. Many of the chemicals were found to be strong reproductive toxicants that have yet to be tested in mammals. Chemicals having affect before meiosis I division vs. meiosis II division were identified for 16 gametogenesis-specific chemicals. Finally, we demonstrate that in general yeast reproductive toxicity correlates well with published reproductive toxicity in mammals illustrating the promise of this NAM to quickly assess chemicals to prioritize the evaluation for human reproductive harm.

Evaluating associations of bisphenol and phthalate exposure with time to pregnancy and subfecundity in a New York City pregnancy cohort.

It is important to understand the impact of consumer chemical exposure and fecundity, a couple's measure of probability of successful conception, given approximately 15% of couples experience infertility. Prior research has generally found null associations between bisphenol and phthalate exposure and fecundability, measured via time to pregnancy (TTP). However, this research has not been updated with current chemical exposures and have often lacked diversity in their study populations. We evaluated the associations between common bisphenol and phthalate chemical exposure groups and TTP as well as subfecundity (TTP>12 months) in the New York University Children's Health Study, a diverse pregnancy cohort from 2016 onward. Using first-trimester spot-urine samples to measure chemical exposure and self-reported TTP from first-trimester questionnaires, we observed a significant adverse association between total bisphenol exposure and certain phthalate groups on TTP and odds of subfecundity. Furthermore, in a mixtures analysis to explore the joint effects of the chemical groups on the outcomes, we found evidence of a potential interaction between total bisphenol exposure and low-molecular weight phthalates on TTP. Future research should continue to update our knowledge regarding the complex and potentially interacting effects of these chemicals on reproductive health.

The effect of bisphenols on sex and thyroid hormone concentrations in cord blood among newborns.

This study aims to investigate the associations of bisphenols with sex and thyroid hormones in cord blood among newborns. Four bisphenols, three hormones related to gonadal function, and four parameters related to thyroid function were measured in umbilical cord blood in 378 mother-newborn pairs. Multivariable linear regression, quantile-based g-computation (QGC), and Bayesian kernel machine regression were used. In the multivariable linear regression, bisphenol A (BPA) was associated with increased testosterone (TT) (regression coefficient, ß = 0.049, 95% confidence interval, CI: 0.013,0.085; p = 0.007) and free tri-iodothyronine (FT3) levels (ß = 0.019, 95% CI: 0.003, 0.035; p = 0.023), and decreased thyroid peroxidase antibody (TPOAb) (ß = -0.053, 95% CI: 0.098, -0.008; p = 0.021). Consistently associations were observed in males, except TT, which was observed in females, and bisphenol AF (BPAF) was associated with decreased follicle-stimulating hormone (FSH) in females. These associations were also observed in a mixture of bisphenols. Moreover, we observed maternal prepregnancy body mass index (BMI) and delivery mode disparity in the relationship between bisphenols and sex and thyroid hormones. This study suggests that bisphenols may exert effects on sex and thyroid hormones in newborns, the effect may vary with sex differences, maternal prepregnancy BMI, and delivery mode.

Exposure to BPA and BPS during pregnancy disrupts the bone mineralization in the offspring.

Exposure to plastic-derived estrogen-mimicking endocrine-disrupting bisphenols can have a long-lasting effect on bone health. However, gestational exposure to bisphenol A (BPA) and its analogue, bisphenol S (BPS), on offspring's bone mineralization is unclear. The effects of in-utero bisphenol exposure were examined on the offspring's bone parameters. BPA and BPS (0.0, 0.4 µg/kg bw) were administered to pregnant Wistar rats via oral gavage from gestational day 4-21. Maternal exposure to BPA and BPS increased bone mineral content and density in the offspring aged 30 and 90 days (P < 0.05). Plasma analysis revealed that alkaline phosphatase, and Gla-type osteocalcin were significantly elevated in the BPS-exposed offspring (P < 0.05). The expression of BMP1, BMP4, and their signaling mediators SMAD1 mRNAs were decreased in BPS-exposed osteoblast SaOS-2 cells (P < 0.05). The expression of extracellular matrix proteins such as ALPL, COL1A1, DMP1, and FN1 were downregulated (P < 0.05). Bisphenol co-incubation with noggin decreased TGF-ß1 expression, indicating its involvement in bone mineralization. Altered mineralization could be due to dysregulated expression of bone morphogenetic proteins and signalling mediators in the osteoblast cells. Thus, bisphenol exposure during gestation altered growth and bone mineralization in the offspring, possibly by modulating the expression of Smad-dependent BMP/TGF-ß1 signalling mediators.