Exposure to UV-B filter octylmethoxycinnamate and human health effects: Focus on endocrine disruptor actions.

Human skin is the first line of photoprotection against UV radiation. However, despite having its defence mechanisms, the photoprotection that the skin exerts is not enough. To protect human skin, the inclusion of UV filters in the cosmetic industry has grown significantly as a photoprotection strategy. Octylmethoxycinnamate, also designated by octinoxate, or 2-ethylhexyl-4-methoxycinnamate (CAS number: 5466-77-3) is one of the most widely used UV-B filter in the cosmetic industry. The toxic effects of OMC have alarmed the public, but there is still no consensus in the scientific community about its use. This article aims to provide an overview of the UV filters' photoprotection, emphasizing the OMC and the possible negative effects it may have on the public health. Moreover, the current legislation will be addressed. In summary, the recommendations should be rethought to assess their risk-benefit, since the existing literature warns us to endocrine-disrupting effects of OMC. Further studies should be focus on the toxicity of OMC alone, in mixture and should consider its degradation products, to improve the knowledge of its risk assessment as EDC.

The physiological and biochemical basis of potency thresholds modeled using human estrogen receptor alpha: implications for identifying endocrine disruptors.

The endocrine system functions by interactions between ligands and receptors. Ligands exhibit potency for binding to and interacting with receptors. Potency is the product of affinity and efficacy. Potency and physiological concentration determine the ability of a ligand to produce physiological effects. The kinetic behavior of ligand-receptor interactions conforms to the laws of mass action. The laws of mass action define the relationship between the affinity of a ligand and the fraction of cognate receptors that it occupies at any physiological concentration. We previously identified the minimum ligand potency required to produce clinically observable estrogenic agonist effects via the human estrogen receptor-alpha (ERα). By examining data on botanical estrogens and dietary supplements, we demonstrated that ERα ligands with potency lower than one one-thousandth that of the primary endogenous hormone 17ß-estradiol (E2) do not produce clinically observable estrogenic effects. This allowed us to propose a Human-Relevant Potency Threshold (HRPT) for ERα ligands of 1 × 10-4 relative to E2. Here, we test the hypothesis that the HRPT for ERα arises from the receptor occupancy by the normal metabolic milieu of endogenous ERα ligands. The metabolic milieu comprises precursors to hormones, metabolites of hormones, and other normal products of metabolism. We have calculated fractional receptor occupancies for ERα ligands with potencies below and above the previously established HRPT when normal circulating levels of some endogenous ERα ligands and E2 were also present. Fractional receptor occupancy calculations showed that individual ERα ligands with potencies more than tenfold higher than the HRPT can compete for occupancy at ERα against individual components of the endogenous metabolic milieu and against mixtures of those components at concentrations found naturally in human blood. Ligands with potencies less than tenfold higher than the HRPT were unable to compete successfully for ERα. These results show that the HRPT for ERα agonism (10-4 relative to E2) proposed previously is quite conservative and should be considered strong evidence against the potential for disruption of the estrogenic pathway. For chemicals with potency 10-3 of E2, the potential for estrogenic endocrine disruption must be considered equivocal and subject to the presence of corroborative evidence. Most importantly, this work demonstrates that the endogenous metabolic milieu is responsible for the observed ERα agonist HRPT, that this HRPT applies also to ERα antagonists, and it provides a compelling mechanistic explanation for the HRPT that is grounded in basic principles of molecular kinetics using well characterized properties and concentrations of endogenous components of normal metabolism.

Fetal and Infancy Exposure to Phenols, Parabens, and Phthalates and Anthropometric Measurements up to 36 Months, in the Longitudinal SEPAGES Cohort.

BACKGROUND: Endocrine-disrupting chemicals may play a role in adiposity development during childhood. Until now literature in this scope suffers from methodologic limitations in exposure assessment using one or few urine samples and missing assessment during the infancy period. OBJECTIVES: We investigated the associations between early-life exposure to quickly metabolized chemicals and post-natal growth, relying on repeated within-subject urine collections over pregnancy and infancy. METHODS: We studied the associations of four phenols, four parabens, seven phthalates, and one nonphthalate plasticizer from weekly pooled urine samples collected from the mother during second and third trimesters (median 18 and 34 gestational weeks, respectively) and infant at 2 and 12 months of age, and child growth until 36 months. We relied on repeated measures of height, weight and head circumference from study visits and the child health booklet to predict growth outcomes at 3 and 36 months using the Jenss-Bayley nonlinear mixed model. We assessed associations with individual chemicals using adjusted linear regression and mixtures of chemicals using a Bayesian kernel machine regression model. RESULTS: The unipollutant analysis revealed few associations. Bisphenol S (BPS) at second trimester was positively associated with all infant growth parameters at 3 and 36 months, with similar patterns between exposure at third trimester and all infant growth parameters at 3 months. Mono-n-butyl phthalate (MnBP) at 12 months was positively associated with body mass index (BMI), weight, and head circumference at 36 months. Mixture analysis revealed positive associations between exposure at 12 months and BMI and weight at 36 months, with MnBP showing the highest effect size within the mixture. CONCLUSIONS: This study suggests that exposure in early infancy may be associated with increased weight and BMI in early childhood, which are risk factors of obesity in later life. Furthermore, this study highlighted the impact of BPS, a compound replacing bisphenol A, which has never been studied in this context. https://doi.org/10.1289/EHP13644.

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.

Comprehensive review of emerging contaminants: Detection technologies, environmental impact, and management strategies.

Emerging contaminants (ECs) are a diverse group of unregulated pollutants increasingly present in the environment. These contaminants, including pharmaceuticals, personal care products, endocrine disruptors, and industrial chemicals, can enter the environment through various pathways and persist, accumulating in the food chain and posing risks to ecosystems and human health. This comprehensive review examines the chemical characteristics, sources, and varieties of ECs. It critically evaluates the current understanding of their environmental and health impacts, highlighting recent advancements and challenges in detection and analysis. The review also assesses existing regulations and policies, identifying shortcomings and proposing potential enhancements. ECs pose significant risks to wildlife and ecosystems by disrupting animal hormones, causing genetic alterations that diminish diversity and resilience, and altering soil nutrient dynamics and the physical environment. Furthermore, ECs present increasing risks to human health, including hormonal disruptions, antibiotic resistance, endocrine disruption, neurological effects, carcinogenic effects, and other long-term impacts. To address these critical issues, the review offers recommendations for future research, emphasizing areas requiring further investigation to comprehend the full implications of these contaminants. It also suggests increased funding and support for research, development of advanced detection technologies, establishment of standardized methods, adoption of precautionary regulations, enhanced public awareness and education, cross-sectoral collaboration, and integration of scientific research into policy-making. By implementing these solutions, we can improve our ability to detect, monitor, and manage ECs, reducing environmental and public health risks.

Environmental BaP/BPDE suppressed trophoblast cell invasion/migration and induced miscarriage by down-regulating lnc-HZ01/MEST/VIM axis.

Environmental benzo(a)pyrene (BaP) and itsmetabolite benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), classic endocrine disrupting chemical and persistent organic pollutant, could cause miscarriage. However, the detailed mechanisms are still largely unclear and should be further explored. In this study, we discovered that exposure of trophoblast cells with BPDE could suppressed cell invasion/migration by inhibiting MEST/VIM (Vimentin) pathway. Moreover, BPDE exposure also increased lnc-HZ01 expression level, which further inhibited MEST/VIM pathway and then suppressed invasion/migration. Knockdown of lnc-HZ01 or overexpression of MEST could efficiently rescue invasion/migration of BPDE-exposed Swan 71 cells. Furthermore, lnc-HZ01 was highly expressed and MEST/VIM were lowly expressed in recurrent miscarriage (RM) villous tissues compared with healthy control (HC) group. Finally, we also found that BaP exposure inhibited murine Mest/Vim pathway in placental tissues and induced miscarriage in BaP-exposed mice. Therefore, the regulatory mechanisms were similar in BPDE-exposed human trophoblast cells, RM villous tissues, and placental tissues of BaP-exposed mice with miscarriage, building a bridge to connect BaP/BPDE exposure, invasion/migration, and miscarriage. This study provided novel insights in the toxicological effects and molecular mechanisms of BaP/BPDE-induced miscarriage, which is helpful for better elucidating the toxicological risks of BaP/BPDE on female reproduction.

Hepatic toxicity prediction of bisphenol analogs by machine learning strategy.

Toxicological studies have demonstrated the hepatic toxicity of several bisphenol analogs (BPs), a prevalent type of endocrine disruptor. The development of Adverse Outcome Pathway (AOP) has substantially contributed to the rapid risk assessment for human health. However, the lack of in vitro and in vivo data for the emerging BPs has limited the hazard assessment of these synthetic chemicals. Here, we aimed to develop a new strategy to rapidly predict BPs' hepatotoxicity using network analysis coupled with machine learning models. Considering the structural and functional similarities shared by BPs with Bisphenol A (BPA), we first integrated hepatic disease related genes from multiple databases into BPA-Gene-Phenotype-hepatic toxicity network and subjected it to the computational AOP (cAOP). Through cAOP network and conventional machine learning approaches, we scored the hepatotoxicity of 20 emerging BPs and provided new insights into how BPs' structure features contributed to biologic functions with limited experimental data. Additionally, we assessed the interactions between emerging BPs and ESR1 using molecular docking and proposed an AOP framework wherein ESR1 was a molecular initiating event. Overall, our study provides a computational approach to predict the hepatotoxicity of emerging BPs.

Bisphenol A and its structural analogues exhibit differential potential to induce mitochondrial dysfunction and apoptosis in human granulosa cells.

Bisphenol A (BPA) is an endocrine disruptor strongly associated with ovarian dysfunction. BPA is being substituted by structurally similar chemicals, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). However, the toxicity of these analogues in female reproduction remains largely unknown. This study evaluated the effects of BPA and its analogues BPS, BPF, and BPAF on the mitochondrial mass and function, oxidative stress, and their potential to induce apoptosis of human granulosa cells (KGN cells). BPA and its analogues, especially BPA and BPAF, significantly decreased mitochondrial activity and cell viability. The potential of bisphenols to reduce mitochondrial mass and function differed in the following order: BPAF > BPA > BPF > BPS. Flow cytometry revealed that exposure to bisphenols significantly increased mitochondrial ROS levels and increased mitochondrial Ca2+ levels. Thus, bisphenols exposure causes mitochondrial stress in KGN cells. At the same time, bisphenols exposure significantly induced apoptosis. These results thus emphasize the toxicity of these bisphenols to cells. Our study suggests the action mechanism of BPA and its analogues in damage caused to ovarian granulosa cells. Additionally, these novel analogues may be regrettable substitutes, and the biological effects and potential risks of BPA alternatives must be evaluated.

Electrochemical degradation of diclofenac generates unexpected thyroidogenic transformation products: Implications for environmental risk assessment.

Diclofenac (DCF) is an environmentally persistent, nonsteroidal anti-inflammatory drug (NSAID) with thyroid disrupting properties. Electrochemical advanced oxidation processes (eAOPs) can efficiently remove NSAIDs from wastewater. However, eAOPs can generate transformation products (TPs) with unknown chemical and biological characteristics. In this study, DCF was electrochemically degraded using a boron-doped diamond anode. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry was used to analyze the TPs of DCF and elucidate its potential degradation pathways. The biological impact of DCF and its TPs was evaluated using the Xenopus Eleutheroembryo Thyroid Assay, employing a transgenic amphibian model to assess thyroid axis activity. As DCF degradation progressed, in vivo thyroid activity transitioned from anti-thyroid in non-treated samples to pro-thyroid in intermediately treated samples, implying the emergence of thyroid-active TPs with distinct modes of action compared to DCF. Molecular docking analysis revealed that certain TPs bind to the thyroid receptor, potentially triggering thyroid hormone-like responses. Moreover, acute toxicity occurred in intermediately degraded samples, indicating the generation of TPs exhibiting higher toxicity than DCF. Both acute toxicity and thyroid effects were mitigated with a prolonged degradation time. This study highlights the importance of integrating in vivo bioassays in the environmental risk assessment of novel degradation processes.

Recognizing high-priority disinfection byproducts based on experimental and predicted endocrine disrupting data: Virtual screening and in vitro study.

So far, about 130 disinfection by-products (DBPs) and several DBPs-groups have had their potential endocrine-disrupting effects tested on some endocrine endpoints. However, it is still not clear which specific DBPs, DBPs-groups/subgroups may be the most toxic substances or groups/subgroups for any given endocrine endpoint. In this study, we attempt to address this issue. First, a list of relevant DBPs was updated, and 1187 DBPs belonging to 4 main-groups (aliphatic, aromatic, alicyclic, heterocyclic) and 84 subgroups were described. Then, the high-priority endocrine endpoints, DBPs-groups/subgroups, and specific DBPs were determined from 18 endpoints, 4 main-groups, 84 subgroups, and 1187 specific DBPs by a virtual-screening method. The results demonstrate that most of DBPs could not disturb the endocrine endpoints in question because the proportion of active compounds associated with the endocrine endpoints ranged from 0 (human thyroid receptor beta) to 32% (human transthyretin (hTTR)). All the endpoints with a proportion of active compounds greater than 10% belonged to the thyroid system, highlighting that the potential disrupting effects of DBPs on the thyroid system should be given more attention. The aromatic and alicyclic DBPs may have higher priority than that of aliphatic and heterocyclic DBPs by considering the activity rate and potential for disrupting effects. There were 2 (halophenols and estrogen DBPs), 12, and 24 subgroups that belonged to high, moderate, and low priority classes, respectively. For individual DBPs, there were 23 (2%), 193 (16%), and 971 (82%) DBPs belonging to the high, moderate, and low priority groups, respectively. Lastly, the hTTR binding affinity of 4 DBPs was determined by an in vitro assay and all the tested DBPs exhibited dose-dependent binding potency with hTTR, which was consistent with the predicted result. Thus, more efforts should be performed to reveal the potential endocrine disruption of those high research-priority main-groups, subgroups, and individual DBPs.

Exploring a mechanism-based approach for the identification of endocrine disruptors using Adverse Outcome Pathways (AOPs) and New Approach Methodologies (NAMs) : A perfluorooctane sulfonic acid case study.

Endocrine disruptors (EDs) pose a serious threat to human health and the environment and require a comprehensive evaluation to be identified. The identification of EDs require a substantial amount of data, both in vitro and in vivo, due to the current scientific criteria in the EU. At the same time, the EU strives to reduce animal testing due to concerns regarding animal welfare and sensitivity of animal studies to adequately detect adverse effects relevant for human health. Perfluorooctane sulfonic acid (PFOS) is a persistent organic pollutant that is suspected to be an ED based on academic research, however it is not identified as such from a regulatory perspective. It has previously been shown that PFOS has the potential to cause neurotoxicity as well as affect the thyroid system, and it is known that specific thyroid hormone levels are critical in the development of the brain during. In this work, the aim was to evaluate a mechanism-based approach to identify ED properties of PFOS based on the Adverse Outcome Pathway (AOP) framework and using New Approach Methods (NAMs), by comparing this approach to an ED assessment based on the currently available guidance document. An AOP network (AOPN) was generated for the thyroid modality, and AOPs leading to developmental neurotoxicity (DNT) were identified. A literature search and screening process based on the AOPN, and systematic review methodology, was performed, followed by a rigorous Weight-of-Evidence (WoE) assessment. Evidence was mapped back onto the AOPN used for the literature search, to identify possible endocrine Modes-of-Action (MoAs) for PFOS and data gaps in the two assessments. It could be concluded that PFOS fulfils the criteria for ED classification in the standard ED assessment, but not in the mechanism-based assessment. The need for quantitative information, such as quantitative AOPs, for the mechanism-based approach is discussed. The possibility of a directly neurotoxic alternative MoA was also highlighted based on available in vitro data. Opportunities and challenges with implementing AOPs and NAMs into the regulatory assessment of EDs, and assessing hazard in the Next Generation Risk Assessment, is discussed. This case study exploring the mechanism-based approach to ED identification represents an important step toward more accurate and predictive assessment of EDs based on AOPs and NAMs, and to the Next Generation Risk Assessment (NGRA) concept.

The research progress on the impact of antibiotics on the male reproductive system.

Antibiotics are extensively utilized in the livestock and poultry industry and can accumulate in animals and the environment, leading to potential health risks for humans via food and water consumption. Research on antibiotic toxicity, particularly their impact as endocrine disruptors on the male reproductive system, is still in its nascent stages. This review highlights the toxic effect of antibiotics on the male reproductive system, detailing the common routes of exposure and the detrimental impact and mechanisms of various antibiotic classes. Additionally, it discusses the protective role of food-derived active substances against the reproductive toxicity induced by antibiotics. This review aims to raise awareness about the reproductive toxicity of antibiotics in males and to outline the challenges that must be addressed in future research.

Estetrol/drospirenone versus 17α-ethinylestradiol/drospirenone: An extended one generation test to evaluate the endocrine disruption potential on zebrafish (Danio rerio).

Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic wildlife by their capacity to disrupt physiological mechanisms. In this study, the endocrine disruptive potential of two mixtures, 17α-ethinylestradiol (EE2), a synthetic oestrogen, or estetrol (E4), a natural oestrogen, with the progestin drospirenone (DRSP) have been characterised in three generations of zebrafish, according to an adapted Medaka Extended One Generation Reproduction Test. Zebrafish (Danio rerio) were exposed to a range of concentrations of EE2/DRSP and E4/DRSP (∼1×, ∼3×, ∼10× and ∼30× predicted environmental concentration, PEC). Survival, growth, hatching success, fecundity, fertilisation success, vitellogenin (VTG), gonad histopathology, sex differentiation, and transcriptional analysis of genes related to gonadal sex steroid hormones synthesis were assessed. In the F0 generation, exposure to EE2/DRSP at ∼10 and ∼30× PEC decreased fecundity and increased male VTG concentrations. The highest concentration of EE2/DRSP also affected VTG concentrations in female zebrafish and the expression of genes implicated in steroid hormones synthesis. In the F1 generation, sex determination was impaired in fish exposed to EE2/DRSP at concentrations as low as ∼3× PEC. Decreased fecundity and fertility, and abnormal gonadal histopathology were also observed. No effects were observed in the F2 generation. In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (∼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation. Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP.

Paternal exposures to endocrine-disrupting chemicals induce intergenerational epigenetic influences on offspring: A review.

Endocrine-disrupting chemicals (EDCs) are ubiquitous in ecological environments and have become a great issue of public health concern since the 1990 s. There is a deep scientific understanding of the toxicity of EDCs. However, recent studies have found that the abnormal physiological functions of the parents caused by EDCs could be transmitted to their unexposed offspring, leading to intergenerational toxicity. We questioned whether sustained epigenetic changes occur through the male germline. In this review, we (1) systematically searched the available research on the intergenerational impacts of EDCs in aquatic and mammal organisms, including 42 articles, (2) summarized the intergenerational genetic effects, such as decreased offspring survival, abnormal reproductive dysfunction, metabolic disorders, and behavioral abnormalities, (3) summarized the mechanisms of intergenerational toxicity through paternal interactions, and (4) propose suggestions on future research directions to develop a deeper understanding of the ecological risk of EDCs.

Maternal exposure to tributyltin alters the breast milk, hormonal profile, and thyroid morphology of dams and induces sex-specific changes in neonate rat offspring.

Tributyltin (TBT) is the chemical substance commonly used worldwide to prevent biofouling of vessels. Due to its ability to bioaccumulate and biomagnify, even after being banned, significant concentrations of TBT can be detected in sediment, affecting marine and human life. Although studies have shown that direct exposure to TBT alters physiological parameters in mammals, the relationship between exposure to TBT during pregnancy and lactation, considered critical windows for metabolic programming, has not been fully elucidated. Our hypothesis is that offspring whose mothers were exposed to TBT during critical stages of development may exhibit dysfunctions in endocrine-metabolic parameters. We used pregnant Wistar rats that were divided into groups and received the following treatments from gestational day 7 until the end of lactation by intragastric gavage: vehicle (ethanol 0.01%; Control), low TBT dose (100 ng/kg of body weight (bw)/day; TBT100ng) and high TBT dose (1000 ng/kg bw/day; TBT1000ng). Dams and offspring at birth and weaning (21 days old) were studied. Maternal exposure to TBT promoted dose-dependent changes in dams. The findings for adiposity, milk composition and lipid profile were more pronounced in TBT100 ng dam; however, thyroid morphology was altered in TBT1000 ng dam. Female offspring were differentially affected by the dose of exposure. At birth, females in the TBT100ng group had low body weight, lower naso-anal length (NAL), and higher plasma T4, and at weaning, females in the TBT100ng group had lower insulin and leptin levels. Females in the TBT1000ng group had lower NAL at birth and lower leptinemia and weight of white adipose tissue at weaning. Male offspring from TBT groups showed high T3 at birth, without biometric alterations at birth or weaning. Despite these findings, both sexes exhibited dose-dependent morphological changes in the thyroid gland. Thus, maternal exposure to TBT constitutes an important route of contamination for both dams and offspring.

Market analysis of the presence of endocrine disrupting chemicals in cosmetic products intended for oncological patients and other vulnerable groups.

There is growing concern about the presence of endocrine disrupting chemicals (EDCs) in cosmetics. We aimed to identify the main cosmetic ingredients with suspected endocrine-disrupting properties, and analyse their presence in current marketed products. Particular attention was given to products intended for susceptible (due to physiological status) and vulnerable (due to specific pathologies) groups with a view to informing cosmetologists and related health professionals of the scientific basis and current status of any concerns. Suspected EDCs used as cosmetic ingredients, included in lists published by regulatory agencies, were documented and investigated by weight of evidence analysis based on endocrine-related toxicity studies. In total, 49 suspected EDCs were identified from a sample of over a thousand cosmetic products marketed in the European Union. Suspected EDCs were found in approximately one third of products, with a similar frequency in products intended for susceptible and vulnerable groups. Avobenzone (CAS number:70356-09-1), octisalate (CAS number: 118-60-5), and butylated hydroxytoluene (CAS number: 128-37-0) were mostly commonly identified. The presence of EDCs was particularly high for sun care cosmetic products. Our results highlight potentially significant exposure through cosmetics to substances currently studied by regulatory institutions as suspected endocrine disrupters. EDCs are not yet universally regulated, and informing health professionals and educating the population as a precaution are options to reduce individual exposure levels, especially in vulnerable and susceptible groups. Special recommendations are needed for products intended for oncological patients.

Computational framework for identifying and evaluating mutagenic and xenoestrogenic potential of food additives.

Food additives are chemicals incorporated in food to enhance its flavor, color and prevent spoilage. Some of these are associated with substantial health hazards, including developmental disorders, increase cancer risk, and hormone disruption. Hence, this study aimed to comprehend the in-silico toxicology framework for evaluating mutagenic and xenoestrogenic potential of food additives and their association with breast cancer. A total of 2885 food additives were screened for toxicity based on Threshold of Toxicological Concern (TTC), mutagenicity endpoint prediction, and mutagenic structural alerts/toxicophores identification. Ten food additives were identified as having mutagenic potential based on toxicity screening. Furthermore, Protein-Protein Interaction (PPI) analysis identified ESR1, as a key hub gene in breast cancer. KEGG pathway analysis verified that ESR1 plays a significant role in breast cancer pathogenesis. Additionally, competitive interaction studies of the predicted potential mutagenic food additives with the estrogen receptor-α were evaluated at agonist and antagonist binding sites. Indole, Dichloromethane, Trichloroethylene, Quinoline, 6-methyl quinoline, Ethyl nitrite, and 4-methyl quinoline could act as agonists, and Paraldehyde, Azodicarbonamide, and 2-acetylfuranmay as antagonists. The systematic risk assessment framework reported in this study enables the exploration of mutagenic and xenoestrogenic potential associated with food additives for hazard identification and management.

Maslinic acid supplementation prevents di(2-ethylhexyl) phthalate-induced apoptosis via PRDX6 in peritubular myoid cells of Chinese forest musk deer.

Chinese forest musk deer (FMD), an endangered species, have exhibited low reproductive rates even in captivity due to stress conditions. Investigation revealed the presence of di(2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor, in the serum and skin of captive FMDs. Feeding FMDs with maslinic acid (MA) has been observed to alleviate the stress response and improve reproductive rates, although the precise molecular mechanisms remain unclear. Therefore, this study aims to investigate the molecular mechanisms underlying the alleviation of DEHP-induced oxidative stress and cell apoptosis in primary peritubular myoid cells (PMCs) through MA intake. Primary PMCs were isolated and exposed to DEHP in vitro. The results demonstrated that DEHP significantly suppressed antioxidant levels and promoted cell apoptosis in primary PMCs. Moreover, interfering with the expression of PRDX6 was found to induce excessive reactive oxygen species (ROS) production and cell apoptosis in primary PMCs. Supplementation with MA significantly upregulated the expression of PRDX6, thereby attenuating DEHP-induced oxidative stress and cell apoptosis in primary PMCs. These findings provide a theoretical foundation for mitigating stress levels and enhancing reproductive capacity of in captive FMDs.

Reproductive and transgenerational toxicity of bisphenol S exposure in pregnant rats: Insights into hormonal imbalance and steroid biosynthesis pathway disruption.

Bisphenol S (BPS) is an alternative chemical to bisphenol A commonly used in food packaging materials. It raises concerns due to potential adverse effects on human health. However, limited evidence exists regarding reproductive toxicity from BPS exposure, and the mechanism of associated transgenerational toxicity remains unclear. In this study, pregnant SD rats were exposed to two different doses of BPS (0.05 or 20 mg/kg) from GD6 to PND21. The objective was to investigate reproductive and transmissible toxicity induced by BPS, explore endocrine effects, and uncover potential underlying mechanisms in rats. Perinatal exposure to BPS in the F0 generation significantly decreased the rate of body weight, ovarian organ coefficient, and growth and development of the F1 generation. Notably, these changes included abnormal increases in body weight and length, estrous cycle disruption, and embryonic dysplasia in F1. 4D-DIA proteomic and PRM analyses revealed that exposure to 20 mg/kg group significantly altered the expression of proteins, such as Lhcgr and Akr1c3, within the steroid biosynthetic pathway. This led to elevated levels of FSH and LH in the blood. The hypothalamic-pituitary-ovarian (HPO) axis, responsible for promoting fertility through the cyclic secretion of gonadotropins and steroid hormones, was affected. RT-qPCR and Western blot results demonstrated that the expression of GnRH in the hypothalamus was decreased, the GnRHR in the pituitary gland was decreased, and the expression of FSHß and LHß in the pituitary gland was increased. Overall, BPS exposure disrupts the HPO axis, hormone levels, and steroid biosynthesis in the ovaries, affecting offspring development and fertility. This study provides new insights into the potential effects of BPS exposure on the reproductive function of the body and its relevant mechanisms of action.

Estrogenic endocrine disruptor exposure directly impacts erectile function.

Erectile dysfunction (ED) is an extremely prevalent condition which significantly impacts quality of life. The rapid increase of ED in recent decades suggests the existence of unidentified environmental risk factors contributing to this condition. Endocrine Disrupting Chemicals (EDCs) are one likely candidate, given that development and function of the erectile tissues are hormonally dependent. We use the estrogenic-EDC diethylstilbestrol (DES) to model how widespread estrogenic-EDC exposure may impact erectile function in humans. Here we show that male mice chronically exposed to DES exhibit abnormal contractility of the erectile tissue, indicative of ED. The treatment did not affect systemic testosterone production yet significantly increased estrogen receptor α (Esr1) expression in the primary erectile tissue, suggesting EDCs directly impact erectile function. In response, we isolated the erectile tissue from mice and briefly incubated them with the estrogenic-EDCs DES or genistein (a phytoestrogen). These acute-direct exposures similarly caused a significant reduction in erectile tissue contractility, again indicative of ED. Overall, these findings demonstrate a direct link between estrogenic EDCs and erectile dysfunction and show that both chronic and acute estrogenic exposures are likely risk factors for this condition.