Endocrine-disrupting Activity Research Articles

Effective adaptation of flight muscles to tebuconazole-induced oxidative stress in honey bees.

The widespread and excessive agricultural use of azole fungicide tebuconazole poses a major threat to pollinator species including honey bee colonies as highlighted by recent studies. This issue is of growing importance, due to the intensification of modern agriculture and the increasing amount of the applied chemicals, serving as a major and recent problem from both an ecotoxicological and an agricultural point of view. The present study aims to detect the effects of acute sublethal tebuconazole exposure focusing on the redox homeostasis of honey bee flight muscles. The results show that the redox homeostasis, especially the glutathione system, of the exposed animals is severely impaired by the treatment, but flight muscles are able to successfully counteract the detrimental effects by the effective activation of protective processes. This efficient adaptation may have led to overcompensation processes eventually resulting in lower hydrogen peroxide and malondialdehyde concentrations after exposure. It could also be assumed that tebuconazole has a non-monotonic dose-response curve similarly to many other substances with endocrine-disrupting activity concerning parameters such as superoxide dismutase activity or total antioxidant capacity. These findings shed light on the detrimental impact of tebuconazole on the redox balance of honey bee flight muscles, also highlighting, that unlike other organs such as the brain, they may effectively adapt to acute tebuconazole exposure.

A three-dimensional mouse liver organoid platform for assessing EDCs metabolites simulating liver metabolism.

Hepatic metabolism is an important process for evaluate the potential activity and toxicity of endocrine disrupting chemicals (EDCs) metabolites. Organization for Economic Co-operation and Development (OECD) has advocated the development of in vitro assays that mimic in vivo hepatic metabolism to eventually replace classical animal tests. In response to this need, we established a 3D mouse liver organoid (mLO) platform that mimics the animal model and is distinct from existing models. We evaluated the effects the activity of EDC metabolites generated through mLOs based on human cell-based reporter gene assays in addition to existing models. This study emphasizes the importance of hepatic ex-vivo and suggests the need a new metabolic model through a 3D mLOs platform. These results indicate that mLOs provides a novel biological method to screen for potential endocrine-disrupting activities of EDC metabolites.

In silico and in vitro evaluation of potential agonistic and antagonistic estrogenic and androgenic activities of pure cyanotoxins, microcystin-LR and cylindrospermopsin

The potential endocrine disruption activity of cyanotoxins, particularly their effects on estrogen and androgen receptors (ER, AR), remains poorly understood. In the present study, the potential agonistic/antagonistic estrogenic and androgenic activities of MC-LR and CYN have been determined for the first time with validated OECD Test Guidelines No. 455 and 458, respectively. The data show that only MC-LR demonstrated weak estrogenic agonistic effects (LogPC10 value of −9.85 M), while both toxins displayed antagonistic effects on the ER, with LogIC30 values of −4.4 and −6.4 for MC-LR and CYN, respectively. In addition, neither MC-LR nor CYN exhibited agonistic/antagonistic activities in AR. Docking studies revealed potential interactions between both toxins and AR, with CYN showing a higher predicted affinity for this receptor. In vivo studies, particularly those investigating androgen disruption, are warranted to confirm the endocrine disrupting potential of MC-LR and CYN.

Assessment of toxicity and endocrine-disrupting activity of bisphenol analogues during ozone and UV treatments in zebrafish eleutheroembryos

In recent decades, increased regulations on the use of bisphenol A (BPA) have prompted a surge in the use of BPA alternatives. Consequently, a widespread occurrence of BPA substitutes in aquatic environments is currently being detected. While some evidence exists about the degradation of these compounds through various water treatment technologies, the evolution of the resulting toxicity and endocrine-disrupting activity during these processes remains scarcely evaluated. In this study, the acute toxicity and transcriptomic responses in zebrafish eleutheroembryos exposed to selected bisphenols (BPA, bisphenol AF (BPAF) and bisphenol CCl (BPC-Cl)) were assessed during their oxidation by ozone. In addition, the response of zebrafish eleutheroembryos exposed to BPC-Cl treated with UV radiation was also investigated. Results showed that both ozonation and UV treatment effectively reduced the intrinsic toxicity of the studied bisphenols. This was observed with the increase of the survival and swim bladder inflation rates of zebrafish eleutheroembryos, reaching control levels. In concordance with these results, the initially altered mRNA levels in genes related to xenobiotic stimulus (cyp2k18); lipid homeostasis and transport (apoa1a); retinoid metabolism (aldh1a2); neutrophil differentiation (alas1); and oxygen transport (hbae3) in zebrafish eleutheroembryos were generally mitigated during the ozonation and UV treatment of bisphenols. Similarly, the high estrogenicity of these bisphenols, observed by elevated mRNA levels of cyp19a1b, decreased significantly during the ozonation treatment, reaching control levels. On the contrary, an increase in mRNA levels of fads2 and cyp19a1b was observed in animals exposed to BPC-Cl treated with UV radiation. These results suggest that the photolysis products of BPC-Cl may induce disruption of the lipid biosynthesis and estrogenicity. This was further confirmed with RNA-sequencing analysis, which revealed that embryos exposed to BPC-Cl treated with UV radiation presented alterations in mRNA levels of genes specifically related to estrogenic stimulus.

Study on association between human plasma polybrominated diphenyl ethers (PBDEs) and thyroid homeostasis and carcinoma.

Polybrominated diphenyl ethers (PBDEs), a category of persistent organic pollutants (POPs), are ubiquitous in the environment and have been reported to have endocrine-disrupting and tumor-promoting activities. However, the evidence for the correlation between plasma PBDEs levels, thyroid homeostasis and thyroid carcinoma in humans remains limited. Herein, we analyzed eight PBDE congeners in 53 patients undergoing thyroid surgery. BDE-209 was identified as the most abundant PBDE congener in plasma (median, 11.36ng/g lipid). BDE-100 concentration was positively associated with free triiodothyronine (FT3), indicating a potential interference with thyroid function. Point-biserial correlation analysis revealed positive associations between certain plasma PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, and BDE-154) and aggressive pathological parameters. There was no significant correlation between PBDEs and BRAF or RAS mutations in PTC patients, indicating that PBDEs may not directly promote the initiation and progression of thyroid cancer through these genetic mutations. It implies the complexity of the relationship between PBDEs exposure and thyroid cancer development. Although not statistically significant, Bayesian kernel-machine regression (BKMR) analysis of single-exposure effects model found that BDE-47 and BDE-99 were positively associated with the risk of malignant neoplasms. The present study not only contributes to the growing evidence regarding the impact of PBDEs on thyroid function but also provides new insights into the association between exposure to certain PBDE congeners and the aggressive pathological parameters of thyroid cancer. Large-scale prospective studies are still needed to support our findings.

Gestational exposure to organophosphate ester flame retardants and risk of childhood obesity in the environmental influences on child health outcomes consortium

Introduction: Organophosphate esters (OPEs) are increasing in use as flame retardants and plasticizers and concerns have been raised given their endocrine-disrupting activities and possible obesogenic consequences. However, longitudinal studies on gestational OPE exposure and childhood obesity are scarce. This study examined whether OPE levels in maternal urine during pregnancy were associated with the risk of childhood obesity. Methods: OPEs were analyzed in pregnancy urine samples of 5,087 individuals from 14 studies contributing to the Environmental influences on Child Health Outcomes (ECHO) Cohort. BDCPP, DBUP/DIBP, and DPHP, detected in > 80 % of the samples, were modeled continuously and by tertiles; whereas BCPP, BBOEP, and BCETP, detected in 50–80 % of samples, were modeled categorically (not-detected, low, and high). Childhood obesity was defined by BMI z-score ≥ 95th percentile according to WHO (<2 years) and the CDC (≥2 years) metrics. Adjusted modified Poisson regression models assessed childhood obesity risk and the mixture effect was assessed using Bayesian kernel machine regression (BKMR). Results: BMI measurements were available for 3,827 children in infancy (0.5–1.9 years), 3,921 children in early childhood (2.0–4.9 years), and 2,541 children in mid-childhood (5.0–10.0 years). Obesity was present in 16–21 % of children across age groups. In mid-childhood DBUP/DIBP second and third versus first tertiles were associated with increased obesity risk (RR 1.14; 95 % CI: 1.02, 1.28; and RR 1.11; 95 % CI: 0.97, 1.27; respectively); whereas BDCPP second and third versus first tertiles reflected an inverse association with obesity risk (RR 0.85; 95 % CI: 0.80, 0.91 and RR 0.91; 95 % CI: 0.77, 1.07; respectively). No association with obesity risk was observed for DPHP, BCPP, BBOEP, and BCETP. Directions observed were consistent with those seen in BKMR models. Conclusions: This study identified mixed associations between gestational OPE exposure and childhood obesity. Further investigation across a comprehensive range of OPE exposures is warranted.

Exposure of elementary school-aged Brazilian children to bisphenol A: association with demographic, social, and behavioral factors, and a worldwide comparison

Bisphenol A (BPA) is a plasticizer used to synthesize polycarbonate plastics and epoxy resins and is well-known for its endocrine-disrupting action. BPA occurrence in the environment is widespread, and there is a growing concern regarding exposure to this chemical during childhood, given the findings indicating the long-lasting hazards associated with exposure during early life compared to adulthood. We examined urinary BPA concentrations from 319 elementary school-aged Brazilian children, using high-performance liquid chromatography coupled to high-resolution mass spectrometry. We found that urinary BPA was detectable in the majority of children, and that urinary BPA levels were higher among children with lower family income and lower maternal educational levels. BPA levels found herein were compared with those from countries with different regulation policies concerning exposure to BPA. They were similar to those reported from studies conducted in Egypt and Australia. Despite more protective regulatory policies in the European Union, they were similar or lower than those reported in European studies. Our findings indicate that exposure of Brazilian children to BPA is widespread and comparable to or even lower than that of countries with stricter regulatory policies.

The use of in vitro bioassays and chemical screening to assess the impact of a minimally processed vegetable facility on wastewater quality.

Fruit- and vegetable-processing facilities may contaminate wastewater via contaminants found in the produce and disinfecting chemicals used. These contaminants may include agrochemicals, pesticides, and disinfectants such as chlorine and quaternary ammonium compounds (QACs). Some compounds may exhibit harmful endocrine-disrupting activity. This study investigated the impact of a minimally processed vegetable facility on wastewater quality via in vitro bioassays and chemical screening. Estrogen activity was assessed via a yeast estrogen screen (YES), and (anti-)androgenic and glucocorticoid activities were evaluated via an MDA-kb2 reporter gene assay. The samples were screened via gas and liquid chromatography-tandem mass spectrometry (GC-MS/MS and LC-MS/MS) to identify target compounds, and GC coupled with time-of-flight mass spectrometry (GC-TOFMS) was used for non-targeted screening. Sample complexity and chemical profiles were assessed using GC-TOFMS. Estrogenic activity was detected in 16 samples (n = 24) with an upper limit of 595 ± 37ng/L estradiol equivalents (EEqs). The final wastewater before discharge had an EEq of 0.23ng/L, which is within the ecological effect-based trigger value range for the estrogenic activity of wastewater (0.2-0.4ng/L EEq). Androgenic activity was detected in one sample with a dihydrotestosterone equivalent (DHTEq) value of 10 ± 2.7ng/L. No antiandrogenic activity was detected. The GC-MS/MS and LC-MS/MS results indicated the presence of multiple pesticides, nonylphenols, triclocarban, and triclosan. Many of these compounds exhibit estrogenic activity, which may explain the positive YES assay findings. These findings showed that wastewater from the facility contained detergents, disinfectants, and pesticides and displayed hormonal activity. Food-processing facilities release large volumes of wastewater, which may affect the quality of the water eventually being discharged into the environment. We recommend expanding conventional water quality monitoring efforts to include additional factors like endocrine activity and disinfectant byproducts.

Negligible additive effect of environmental concentrations of fragmented polyethylene terephthalate microplastics on the growth and reproductive performance of Java medaka exposed to 17β-estradiol and bisphenol A

To investigate whether environmental concentrations of fragmented polyethylene terephthalate (PET) microplastics (MPs) have additional or combined effects on endocrine-disrupting activity, Java medaka (Oryzias javanicus) were exposed to 17β-estradiol (E2; 5, 10, 50, and 100 ng L−1), bisphenol A (BPA; 5, 10, 50, and 100 µg L−1), and E2 and BPA combined with PET MPs (1 and 100 particles L−1) for 200 days. The growth parameters, such as body length and weight, were significantly decreased by the highest concentrations of E2 and BPA. A significant reduction in egg production was observed in female fish exposed to BPA, with an additive toxic effect of PET MPs. A female-biased sex ratio was observed in fish exposed to both chemicals. Exposure to E2 significantly increased the hepatosomatic index (HSI) in both sexes, while no significant effect was observed in the gonadosomatic index (GSI). Exposure to BPA significantly increased the HSI in female fish and decreased the GSI in both sexes of fish. An additive effect of PET MPs was observed on the GSI value of female exposed to BPA. Significant elevations in vitellogenin (VTG) levels were observed in both sexes due to exposure to E2 and BPA. Additive effects of PET MPs were observed on VTG levels in males exposed to E2 and BPA. Taken together, even long-term treatment with PET MPs induced only a negligible additive effect on the endocrine-disrupting activity in Java medaka at environmentally relevant concentrations.

Endocrine Disruptive Activity and Occurrence of Pharmaceuticals and Viral Content in Water Sources in Melusii Informal Settlement, Pretoria

Endocrine Disruptive Activity and Occurrence of Pharmaceuticals and Viral Content in Water Sources in Melusii Informal Settlement, Pretoria

Effects of combined exposure to two bisphenol plasticizers (BPA and BPB) on Xenopus laevis development

Due to its endocrine disruptive activity, the plastic additive Bisphenol A (BPA) is classified as substance of very high concern (EU ECHA 2017). A correlation between environmental exposure to BPA and congenital defects has been described in humans and in experimental species including the amphibian Xenopus laevis, where severe branchial defects were associated to lethality. The exposure of X. laevis embryos to the BPA analogue bisphenol B (BPB) was recently linked to similar teratogenic effects, with BPB having relative potency about 3 times higher than BPA. The combined BPA-BPB exposure is realistic as both BPA and BPB are detected in human samples and environment. Limited experimental data are available on the combined developmental toxicity of BPA and BPB. The aim of the present work is to evaluate the effects of BPA and BPB mixture in the X. laevis development model, using R-FETAX procedure. The exposure was limited to the first day of development (corresponding to the phylotypic developmental period, common to all vertebrates). Samples were monitored for lethal effects during the full six-day test period and the external morphology was evaluated at the end of the test. Mixture effects were described by modelling, using the PROAST software package. Overall data modelling showed that dose-addiction could not be rejected, suggesting a health concern for co-exposure.

A combined in vitro-in silico method for assessing the androgenic activities of bisphenol A and its analogues

Interactions between endocrine-disruptor chemicals (EDCs) and androgen receptor (AR) have adverse effects on the endocrine system, leading to human reproductive dysfunction. Bisphenol A (BPA) is an EDC that can damage both the environment and human health. Although numerous BPA analogues have been produced as substitutes for BPA, few studies have evaluated their endocrine-disrupting abilities. We assessed the (anti)-androgenic activities of BPA and its analogues using a yeast-based reporter assay. The BPA analogues tested were bisphenol S (BPS), 4-phenylphenol (4PP), 4,4′-(9-fluorenyliden)-diphenol (BPFL), tetramethyl bisphenol F (TMBPF), and tetramethyl bisphenol A (TMBPA). We also conducted molecular docking and dynamics simulations to assess the interactions of BPA and its analogues with the ligand-binding domain of human AR (AR-LBD). Neither BPA nor its analogues had androgenic activity; however, all except BPFL exerted robust anti-androgenic effects. Consistent with the in vitro results, anti-androgenic analogues of BPA formed hydrogen bonding patterns with key residues that differed from the patterns of endogenous hormones, indicating that the analogues display in inappropriate orientations when interacting with the binding pocket of AR-LBD. Our findings indicate that BPA and its analogues disrupt androgen signaling by interacting with the AR-LBD. Overall, BPA and its analogues display endocrine-disrupting activity, which is mediated by AR.

Flavouring Group Evaluation 413 (FGE.413): Naringenin.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of naringenin [FL-no: 16.132] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. No other substances with sufficient structural similarity have been identified in existing FGEs that could be used to support a read-across approach. The information provided on the manufacturing process, the composition and the stability of [FL-no: 16.132] was considered sufficient. From studies carried out with naringenin, the Panel concluded that there is no concern with respect to genotoxicity. The use of naringenin as a flavouring substance at added portions exposure technique (APET) exposure levels is unlikely to pose a risk for drug interaction. For the toxicological evaluation of naringenin, the Panel requested an extended one-generation toxicity study on naringenin, in line with the requirements of the Procedure and to investigate the consequence of a possible endocrine-disrupting activity. The Panel considered that changes in thymus weight, litter size, post-implantation loss and a consistent reduced pup weight in the high-dose F2 generation could not be dismissed and selected therefore, the mid-dose of 1320 mg/kg body weight (bw) per day for the parental males as the no observed adverse effect level (NOAEL) of the study. The exposure estimates for [FL-no: 16.132] (31,500 and 50,000 μg/person per day for children and adults, respectively) were above the threshold of toxicological of concern (TTC) for its structural class (III). Using the NOAEL of 1320 mg/kg bw per day at step A4 of the procedure, margins of exposure (MoE) of 1590 and 630 could be calculated for adults and children, respectively. Based on the calculated MoEs, the Panel concluded that the use of naringenin as a flavouring substance does not raise a safety concern.

Multiplex analysis platform for evaluation of endocrine disruption of emerging contaminants against human steroid hormone receptors using autobioluminescent yeast bioassay: Application to bisphenols

Emerging synthetic or derivative chemicals have drawn global concern due to their potential endocrine-disrupting effects, either as agonists or antagonists or through indirect effects on enzymes of signal transduction pathways. Currently, in vitro screening models are limited to poor tolerance, robustness, high cost and need for sphisticated equipment or complex procedures that require high levels of expertise. Herein, a multiplex analysis platform based on autobioluminescent yeast strains, including BLYhERαS, BLYhERβS, BLYhPRS, BLYhARS, BLYhMRS, and BLYhGRS, was developed for use in easy, rapid, robust, and sensitive screening for potential modulation of endocrine systems. Methods were applied to assess endocrine-disrupting effects of Bisphenol A (BPA) and its alternatives. Disrupting activities of bisphenols (BPs) varied greatly, and some BPA substitutes exerted more potent activities than those of BPA. Most BPs were primarily agonists of ERα and ERβ, while others were antagonists to AR, PR, GR, and MR. BPP and BPM exhibited non-monotonic dose-response relationships toward ERα and ERβ, and BHPF and BPG displayed converse disrupting activities to ERα and ERβ. Overall, the bioassay system provides an efficient tool for comprehensive evaluation of endocrine-disrupting activities of emerging contaminants.

Dimethylcyclosiloxanes in Mobile Smart Terminal Devices: Concentrations, Distributions, Profiles, and Environmental Emissions.

Dimethylcyclosiloxanes (DMCs) are utilized as vital monomers in the synthesis of organosilicon compounds, integral to the manufacture of mobile smart terminal devices. Toxicological studies have revealed potential endocrine-disrupting activity, reproductive toxicity, neurotoxicity, and other toxicities of the DMCs. This study investigated the concentrations and composition profiles of seven DMCs, including hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6), and tetradecamethylcycloheptasiloxane (D7), hexadecamethylcyclooctasiloxane (D8), and octadecamethylcyclononasiloxane (D9) in three types of mobile smart terminal device components (silicone rubber, adhesive, and plastics). Environmental emissions of DMCs from silicone rubber materials were also estimated to improve the recognition of their potential fate within the environment. D5-D9 were widely present in silicone rubber and adhesives with detection rates ranging from 91-95.5% and 50-100%, respectively, while D3 and D4 were more frequently detected in plastics, both showing a detection rate of 61.1%. Silicone rubber had the highest total DMCs (∑7DMCs) and a concentration of 802.2 mg/kg, which were dominated by D7, D8, and D9. DMCs detected in adhesives were dominated by D4, D5, and D6. The estimated emission of ∑DMCs released into the environment in China from silicone rubber used in mobile smart terminal devices exceeds 5000 tons per year. Further studies are needed on the presence of DMCs in various commodities and environmental media to assess their ecological and human health impacts, as well as the toxicological effects of D7-D9 for the appropriate regulation of these chemicals.

An Integrated Approach of Bioassays and Non-Target Screening for the Assessment of Endocrine-Disrupting Activities in Tap Water and Identification of Novel Endocrine-Disrupting Chemicals.

The safety of drinking water is a significant environmental issue of great concern for human health since numerous contaminants are often detected in drinking water and its sources. Boiling is a common household method used to produce relatively high-quality drinking water in some countries and regions. In this study, with the aid of an integrated approach of in vitro bioassays and non-target analysis based on high-resolution mass spectrometry coupled with liquid chromatography, alterations in endocrine-disrupting activities in tap water samples without and with boiling were revealed, as well as the potential endocrine-disrupting chemicals (EDCs) contributing to these alterations were identified. The organic extracts of tap water had no significant (ant)agonistic activities against an estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) at enrichment concentrations of ≤10 times, posing no immediate or acute health risk to humans. However, the presence of agonistic activities against PR and MR and antagonistic activities against ER, PR, GR, and MR in OEs of tap water at relatively higher enrichment concentrations still raise potential health concerns. Boiling effectively reduced antagonistic activities against these steroid hormone receptors (SHRs) but increased estrogenic and glucocorticoid activities in drinking water. Four novel potential EDCs, including one UV filter (phenylbenzimidazole sulfonic acid, PBSA) and three natural metabolites of organisms (beta-hydroxymyristic acid, 12-hydroxyoctadecanoic acid, and isorosmanol) were identified in drinking water samples, each of which showed (ant)agonistic activities against different SHRs. Given the widespread use of UV filters in sunscreens to prevent skin cancer, the health risks posed by PBSA as an identified novel EDC are of concern. Although boiling has been thought to reduce the health risk of drinking water contamination, our findings suggest that boiling may have a more complex effect on the endocrine-disrupting activities of drinking water and, therefore, a more comprehensive assessment is needed.

Predicting the Activity of Unidentified Chemicals in Complementary Bioassays from the HRMS Data to Pinpoint Potential Endocrine Disruptors.

The majority of chemicals detected via nontarget liquid chromatography high-resolution mass spectrometry (HRMS) in environmental samples remain unidentified, challenging the capability of existing machine learning models to pinpoint potential endocrine disruptors (EDs). Here, we predict the activity of unidentified chemicals across 12 bioassays related to EDs within the Tox21 10K dataset. Single- and multi-output models, utilizing various machine learning algorithms and molecular fingerprint features as an input, were trained for this purpose. To evaluate the models under near real-world conditions, Monte Carlo sampling was implemented for the first time. This technique enables the use of probabilistic fingerprint features derived from the experimental HRMS data with SIRIUS+CSI:FingerID as an input for models trained on true binary fingerprint features. Depending on the bioassay, the lowest false-positive rate at 90% recall ranged from 0.251 (sr.mmp, mitochondrial membrane potential) to 0.824 (nr.ar, androgen receptor), which is consistent with the trends observed in the models' performances submitted for the Tox21 Data Challenge. These findings underscore the informativeness of fingerprint features that can be compiled from HRMS in predicting the endocrine-disrupting activity. Moreover, an in-depth SHapley Additive exPlanations analysis unveiled the models' ability to pinpoint structural patterns linked to the modes of action of active chemicals. Despite the superior performance of the single-output models compared to that of the multi-output models, the latter's potential cannot be disregarded for similar tasks in the field of in silico toxicology. This study presents a significant advancement in identifying potentially toxic chemicals within complex mixtures without unambiguous identification and effectively reducing the workload for postprocessing by up to 75% in nontarget HRMS.

A review: Exposure to bisphenol a analogues in non-human primates as a potential cause of endometriosis

Introduction: Bisphenol A is a synthetic compound widely used in the production of polycarbonate plastics and epoxy resins worldwide. As an environmental toxin, it has been reported in plastic equipment and utensils, water bottles and bottle tops, water supply pipes and epoxy resins that coat most of the metal food cans. It is a known endocrine-disrupting chemical and has been progressively replaced by its derivatives including bisphenol S, bisphenol F, bisphenol E, bisphenol AF, bisphenol B and tetramethyl bisphenol F. Bisphenol A and its analogues can bind to estrogen receptors and trigger multiple cellular responses at the organism level. Methods: A comprehensive literature review was done utilising electronic databases of PubMed, Google Scholar, Hinari, Connected papers and Science Direct from 1991 onwards. The articles were only included if they reported original relevant research and were limited to articles written in English. Results: Animal models, including non-human primates, have been used to study their effects on the endocrine system. Its endocrine disruption activity is reported to be the most studied effect in reproductive biology indicating that it may potentially cause endometriosis in females. Though non-human primates are closely related to humans, limited data exists on their associations between Bisphenol A exposure and its analogues and the pathophysiology of endometriosis. Conclusion: Given the current multifaceted knowledge/theory on endometriosis etiology, there is a strong necessity to conduct further biomedical research that utilises non-human primates to study the link between endocrine-disrupting chemicals and its effects on endometriosis.

Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests.

Efforts are being made globally to improve the evaluation and understanding of endocrine-disrupting chemicals. Recognition of their impact on human health and the environment has stimulated attention and research in this field. Various stakeholders, including scientists, regulatory agencies, policymakers, and industry representatives, are collaborating to develop robust methodologies and guidelines for assessing these disruptors. A key aspect of these efforts is the development of standardized testing protocols and guidelines that aim to provide consistent and reliable methods for identifying and characterizing endocrine disruptors. When evaluating the potential endocrine-disrupting activity of chemicals, no single test is capable of detecting all relevant endocrine-disrupting agents. The test battery approach is designed to reduce the risk of false negative results for compounds with toxic potential. A weight-of-evidence approach is therefore necessary for endocrine disruptor evaluation. This approach considers various types of data from multiple sources, assessing the overall strength, consistency, and reliability of the evidence. OECD guidelines are highly regarded for their scientific rigor, transparency, and consensus-based development process. It is crucial to explore and develop new methodologies that can effectively evaluate the risks associated with potential endocrine disruptors. Integrating these methods into a comprehensive weight-of-evidence framework will enhance risk assessments and facilitate informed decisions regarding the regulation and management of these substances, ensuring the protection of human health and the environment from their adverse effects.

Altered Igf2 imprint leads to accelerated adipogenesis and early onset of metabolic syndrome in male mice following gestational arsenic exposure

Developmental exposure to environmental pollutants has been shown to promote adverse health outcomes in offspring. Exposure to heavy metals such as arsenic which also has endocrine-disrupting activity is being increasingly linked with cancers, diabetes, and lately with Metabolic Syndrome (MetS). In this work, we have assessed the effects of preconceptional plus gestational arsenic exposure on the developmental programming of MetS in offspring. In our study, only gestational arsenic exposure led to reduced birth weight, followed by catch-up growth, adiposity, elevated serum triglycerides levels, and hyperglycemia in male offspring. Significant adipocyte dysfunction was observed in offspring with increased hypertrophy, insulin resistance, and chronic inflammation in epididymal white adipose tissue. Adipose tissue regulates the metabolic health of individuals and its dysfunction resulted in elevated serum levels of metabolism-regulating adipokines (Leptin, Resistin) and pro-inflammatory cytokines (PAI-1, TNFα). The progenitor adipose-derived stem cells (AdSCs) from exposed progeny had increased proliferation and adipogenic potential with excess lipid accumulation. We also found increased activation of Akt, ERK1/2 & p38 MAPK molecules in arsenic-exposed AdSCs along with increased levels of phospho-Insulin-like growth factor-1 receptor (p-IGF1R) and its upstream activator Insulin-like growth factor-2 (IGF2). Overexpression of Igf2 was found to be due to arsenic-mediated DNA hypermethylation at the imprinting control region (ICR) located -2kb to −4.4 kb upstream of the H19 gene which caused a reduction in the conserved zinc finger protein (CTCF) occupancy. This further led to persistent activation of the MAPK signaling cascade and enhanced adipogenesis leading to the early onset of MetS in the offspring.