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.

Maternal Di-(2-ethylhexyl)-Phthalate exposure during pregnancy altered energy metabolism in immature offspring and caused hyperglycemia.

Di-(2-ethylhexyl)-phthalate (DEHP), as distinctive endocrine disrupting chemicals, has become a global environmental pollutant harmful to human and animal health. However, the impacts on offspring and mothers with maternal DEHP exposure are largely unknown and the mechanism remains elusive. We established DEHP-exposed maternal mice to investigate the impacts on mother and offspring and illustrate the mechanism from multiple perspectives. Pregnant mice were administered with different doses of DEHP, respectively. Metagenomic sequencing used fecal and transcriptome sequencing using placentas and livers from offspring have been performed, respectively. The results of the histopathology perspective demonstrated that DEHP exposure could disrupt the function of islets impact placentas and fetus development for maternal mice, and cause the disorder of glucose and lipid metabolism for immature offspring mice, resulting in hyperglycemia. The results of the metagenome of gut microbial communities indicated that the dysbiosis of gut microbiota in mother and offspring mice and the dominant phyla transformed through vertical transmission. Transcriptome analysis found DEHP exposure induced mutations of Ahcy and Gstp3, which can damage liver cells and affect the metabolism of the host. DEHP exposure harms pregnant mice and offspring by affecting gene expression and altering metabolism. Our results suggested that exposure of pregnant mice to DEHP during pregnancy and lactation increased the risk of metabolic disorders by altering key genes in liver and gut microbiota, and these results provided new insights into the potential long-term harms of DEHP.

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.

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.

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.

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.

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.

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.

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.

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.

Liquid crystal monomers disrupt photoreceptor patterning of zebrafish larvae via thyroid hormone signaling.

Liquid crystal monomers (LCMs) are the raw material for liquid crystal displays, and their use is steadily increasing in electronic products. Recently, LCMs have been reported to be novel endocrine disrupting chemicals, however, the mechanisms underlying their potential for thyroid hormone disruption and visual toxicity are not well understood. In this study, six widely used fluorinated LCMs (FLCMs) were selected to determine putative mechanisms underlying FLCM-induced toxicity to the zebrafish thyroid and visual systems. Exposure to FLCMs caused damage to retinal structures and reduced cell density of ganglion cell layer, inner nuclear layer, and photoreceptor layer approximately 12.6-46.1%. Exposure to FLCMs also disrupted thyroid hormone levels and perturbed the hypothalamic-pituitary-thyroid axis by affecting key enzymes and protein in zebrafish larvae. A thyroid hormone-dependent GH3 cell viability assay supported the hypothesis that FLCMs act as thyroid hormone disrupting chemicals. It was also determined that FLCMs containing aliphatic ring structures may have a higher potential for T3 antagonism compared to FLCMs without an aliphatic ring. Molecular docking in silico suggested that FLCMs may affect biological functions of thyroxine binding globulin, membrane receptor integrin, and thyroid receptor beta. Lastly, the visual motor response of zebrafish in red- and green-light was significantly inhibited following exposure to FLCMs. Taken together, we demonstrate that FLCMs can act as thyroid hormone disruptors to induce visual dysfunction in zebrafish via several molecular mechanisms.

Impact of benzo[a]pyrene, PCB153 and sex hormones on human ESC-Derived thyroid follicles using single cell transcriptomics.

INTRODUCTION: Endocrine disruptors are compounds of manmade origin able to interfere with the endocrine system and constitute an important environmental concern. Indeed, detrimental effects on thyroid physiology and functioning have been described. Differences exist in the susceptibility of human sexes to the incidence of thyroid disorders, like autoimmune diseases or cancer. METHODS: To study how different hormonal environments impact the thyroid response to endocrine disruptors, we exposed human embryonic stem cell-derived thyroid organoids to physiological concentrations of sex hormones resembling the serum levels of human females post-ovulation or males of reproductive age for three days. Afterwards, we added 10 µM benzo[a]pyrene or PCB153 for 24 h and analyzed the transcriptome changes via single-cell RNA sequencing with differential gene expression and gene ontology analysis. RESULTS: The sex hormones receptors genes AR, ESR1, ESR2 and PGR were expressed at low levels. Among the thyroid markers, only TG resulted downregulated by benzo[a]pyrene or benzo[a]pyrene with the "male" hormones mix. Both hormone mixtures and benzo[a]pyrene alone upregulated ribosomal genes and genes involved in oxidative phosphorylation, while their combination decreased the expression compared to benzo[a]pyrene alone. The "male" mix and benzo[a]pyrene, alone or in combination, upregulated genes involved in lipid transport and metabolism (APOA1, APOC3, APOA4, FABP1, FABP2, FABP6). The combination of "male" hormones and benzo[a]pyrene induced also genes involved in inflammation and NFkB targets. Benzo[a]pyrene upregulated CYP1A1, CYP1B1 and NQO1 irrespective of the hormonal context. The induction was stronger in the "female" mix. Benzo[a]pyrene alone upregulated genes involved in cell cycle regulation, response to reactive oxygen species and apoptosis. PCB153 had a modest effect in presence of "male" hormones, while we did not observe any changes with the "female" mix. CONCLUSION: This work shows how single cell transcriptomics can be applied to selectively study the in vitro effects of endocrine disrupters and their interaction with different hormonal contexts.

Exploring novel insights into the molecular mechanisms underlying Bisphenol A-induced toxicity: A persistent threat to human health.

Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of polycarbonate plastics and epoxy resins, found in numerous consumer products. Despite its widespread use, its potential adverse health effects have raised significant concerns. This review explores the molecular mechanisms and evidence-based literature underlying BPA-induced toxicities and its implications for human health. BPA is an endocrine-disrupting chemical (EDC) which exhibits carcinogenic properties by influencing various receptors, such as ER, AhR, PPARs, LXRs, and RARs. It induces oxidative stress and contributes to cellular dysfunction, inflammation, and DNA damage, ultimately leading to various toxicities including but not limited to reproductive, cardiotoxicity, neurotoxicity, and endocrine toxicity. Moreover, BPA can modify DNA methylation patterns, histone modifications, and non-coding RNA expression, leading to epigenetic changes and contribute to carcinogenesis. Overall, understanding molecular mechanisms of BPA-induced toxicity is crucial for developing effective strategies and policies to mitigate its adverse effects on human health.

Toxicity assessment of dioxins and their transformation by-products from inferred degradation pathways.

Due to the significant POPs characteristics, dioxins caused concern in public health and environmental protection. Evaluating the toxicity risk of dioxin degradation pathways is critical. OCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF, which are highly abundant in the environment and have strong biodegradation capabilities, were selected as precursor molecules in this study. Firstly, their transformation pathways were deduced during the metabolism of biometabolism, microbial aerobic, microbial anaerobic, and photodegradation pathways, and density function theory (DFT) was used to calculate the Gibbs free energy to infer the possibility of the occurrence of the transformation pathway. Secondly, the carcinogenic potential of the precursors and their degradation products was evaluated using the TOPKAT modeling method. With the help of the positive indicator (0-1) normalization method and heat map analysis, a significant increase in the toxic effect of some of the transformation products was found, and it was inferred that it was related to the structure of the transformation products. Meanwhile, the strength of the endocrine disrupting effect of dioxin transformation products was quantitatively assessed using molecular docking and subjective assignment methods, and it was found that dioxin transformation products with a higher content of chlorine atoms and molecules similar to those of thyroid hormones exhibited a higher risk of endocrine disruption. Finally, the environmental health risks caused by each degradation pathway were comprehensively assessed with the help of the negative indicator (1-2) standardization method, which provides a theoretical basis for avoiding the toxicity risks caused by dioxin degradation transformation. In addition, the 3D-QSAR model was used to verify the necessity and rationality of this study. This paper provides theoretical support and reference significance for the toxicity assessment of dioxin degradation by-products from inferred degradation pathways.

Melatonin counteracts polyethylene microplastics induced adreno-cortical damage in male albino rats.

There are various substances that can disrupt the homeostatic mechanisms of the body, defined as endocrine-disrupting chemicals (EDCs). The persistent nature of microplastics (MPs) is a cause for concern due to their ability to accumulate in food chains and widespread use, making their toxic effects particularly alarming. The potential of MPs for disrupting the endocrine system was observed in multiple tissues. Moreover, the adrenal gland is known to be extremely sensitive to EDCs, while with the effect of MPs on the adrenal gland has not previously been studied. This study aimed to highlight the potential polyethylene microplastics (PE-MPs) induced adreno-toxic effects rather than exploring the implicated mechanisms and concluding if melatonin (Mel) can afford protection against PE-MPs induced adreno-toxicity. To fulfill the goal, six groups of rats were used; control, Mel, PE-MPs (3.75 mg/kg), PE-MPs (15 mg/kg), PE-MPs (3.75 mg/kg) +Mel, and PE-MPs (15 mg/kg) +Mel. PE-MPs induced toxic changes in the adrenal cortex, which was evident by increased adrenal weight, histopathological examination, and ultrastructural changes detected by electron microscope. A reduction in serum cortisol and an increase in serum adrenocorticotropic hormone resulted from the adreno-toxic effects of PE-MPs. Mechanisms may include the reduction of steroidogenesis-related genes, as PE-MPs drastically reduce mRNA levels of StAR, Nr0b1, Cyp11A1, as well as Cyp11B1. Also, oxidative stress that results from PE-MPs is associated with higher rates of lipid peroxidation and decreased superoxide dismutase and glutathione. PE-MPs inflammatory effect was illustrated by elevated expression of IL-1ß and NF-kB, detected by immunohistochemical staining, in addition to increased expression of caspase-3 and mRNA of Bax, markers of proapoptotic activity. The impacts of PE-MPs were relatively dose-related, with the higher dose showing more significant toxicity than the lower one. Mel treatment was associated with a substantial amelioration of PE-MPs-induced toxic changes. Collectively, this study fills the knowledge gap about the MPs-induced adrenal cortex and elucidates various related toxic mechanisms. It also supports Mel's potential protective activity through antioxidant, anti-inflammatory, anti-apoptotic, and gene transcription regulatory effects.

Freshwater water quality criteria for phthalate esters and recommendations for the revision of the water quality standards.

With increasing urbanization and rapid industrialization, more and more environmental problems have arisen. Phthalates (PAEs) are the foremost and most widespread plasticizers and are readily emitted from these manufactured products into the environment. PAEs act as endocrine-disrupting chemicals (EDCs) and can have serious impacts on aquatic organisms as well as human health. In this study, the water quality criteria (WQC) of five PAEs (dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP) and di(2-ethylhexyl) phthalate (DEHP)) for freshwater aquatic organisms were developed using a species sensitivity distribution (SSD) and a toxicity percentage ranking (TPR) approach. The results showed that long-term water quality criteria (LWQC) of PAEs using the SSD method could be 13.7, 11.1, 2.8, 7.8, and 0.53 µg/L, respectively. Criteria continuous concentrations (CCC) of PAEs were derived using the TPR method and determined to be 28.4, 13.1, 1.3, 2.5, and 1.6 µg/L, respectively. The five PAEs are commonly measured in China surface waters at concentrations between ng/L and µg/L. DBP, DEHP, and di-n-octyl phthalate (DnOP) were the most frequently detected PAEs, with occurrence rates ranging from 67% to 100%. The ecological risk assessment results of PAEs showed a decreasing order of risk at the national level, DEHP, DBP, DMP, DEP, DnOP. The results of this study will be of great benefit to China and other countries in revising water quality standards for the conservation of aquatic species.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Endocrine toxicity of atrazine and its underlying mechanisms.

Atrazine (ATR) is one of the most widely utilized herbicides globally and is prevalent in the environment due to its extensive use and long half-life. It can infiltrate the human body through drinking water, ingestion, and dermal contact, and has been recognized as an environmental endocrine disruptor. This study aims to comprehensively outline the detrimental impacts of ATR on the endocrine system. Previous research indicates that ATR is harmful to various bodily systems, including the reproductive system, nervous system, adrenal glands, and thyroi d gland. The toxic effects of ATR on the endocrine system and its underlying molecular mechanisms are summarized as follows: influencing the expression of kisspeptin in the HPG axis, consequently affecting steroid synthesis; disrupting DNA synthesis and meiosis, as well as modifying DNA methylation levels, leading to reproductive and developmental toxicity; impacting dopamine by altering Nurr1, VMAT2, and DAT expression, consequently affecting dopamine synthesis and transporter expression, and influencing other neurotransmitters, resulting in neurotoxicity; and changing adipose tissue synthesis and metabolism by reducing basal metabolism, impairing cellular oxidative phosphorylation, and inducing insulin resistance. Additionally, a compilation of natural products used to mitigate the toxic effects of ATR has been provided, encompassing melatonin, curcumin, quercetin, lycopene, flavonoids, vitamin C, vitamin E, and other natural remedies. It is important to note that existing research predominantly relies on in vitro and ex vivo experiments, with limited population-based empirical evidence available.

Zooplankton-based adverse outcome pathways: A tool for assessing endocrine disrupting compounds in aquatic environments.

Endocrine disrupting compounds (EDCs) pose a significant ecological risk, particularly in aquatic ecosystems. EDCs have become a focal point in ecotoxicology, and their identification and regulation have become a priority. Zooplankton have gained global recognition as bioindicators, benefiting from rigorous standardization and regulatory validation processes. This review aims to provide a comprehensive summary of zooplankton-based adverse outcome pathways (AOPs) with a focus on EDCs as toxicants and the utilisation of freshwater zooplankton as bioindicators in ecotoxicological assessments. This review presents case studies in which zooplankton have been used in the development of AOPs, emphasizing the identification of molecular initiating events (MIEs) and key events (KEs) specific to zooplankton exposed to EDCs. Zooplankton-based AOPs may become an important resource for understanding the intricate processes by which EDCs impair the endocrine system. Furthermore, the data sources, experimental approaches, advantages, and challenges associated with zooplankton-based AOPs are discussed. Zooplankton-based AOPs framework can provide vital tools for consolidating toxicological knowledge into a structured toxicity pathway of EDCs, offering a transformative platform for facilitating enhanced risk assessment and chemical regulation.

Reproductive and endocrine-disrupting toxicity of pyrogallol in catfish (Clariasgariepinus).

Endocrine disruptors are synthetic or natural chemicals that can agonize/antagonize hormone receptors or can interfere with the production and secretion of hormones, leading to altered tissue histology and physiology. Pyrogallol is a contaminant widely distributed in aquatic environments that presents health risks to both humans and animals. However, the potential for endocrine disruption by pyrogallol, particularly in fish, are lacking. The purpose of this study was to shed light on how pyrogallol may affect hormone signalling, histopathology, and reproductive outcomes in African catfish Clarias gariepinus. To investigate this, African catfish were exposed to one sublethal concentration of pyrogallol at either 0, 1, 5 or 10 mg/L for 15 days. We then assessed the effects of pyrogallol on the thyroid gland as well as the reproductive system by measuring sex hormone, seminal quality, gonadal histopathology, and histochemistry. Thyroid stimulating hormone and thyroxine showed notable decreases in catfish, and triiodothyronine was decreased with 10 mg/L pyrogallol. Unlike luteinizing hormone, follicle-stimulating hormone was significantly reduced in fish following exposure to pyrogallol relative to controls. Testosterone was also decreased in fish following pyrogallol exposure, whereas 17ß-estradiol increased in catfish exposed to pyrogallol. Additionally, in response to pyrogallol toxicity, sperm quality indices, including count, spermatocrit, motility, and sperm viability were adversely affected in a concentration-dependent manner. Pyrogallol exposure also induced several changes in the gonad following exposure to 1, 5, or 10 mg/L. Deformed tubular structures, vacuolation, thickening of the basement membrane, hypertrophy of the seminiferous tubules, intense melanomacrophage localization, spermatozoa loss, and necrosis were all observed in the testes. In the ovary, atretic follicles, deteriorated mature oocytes, degenerated yolk globules, and an increase in perinucleolar oocytes were observed in catfish exposed to pyrogallol. These findings suggest that pyrogallol may act as endocrine disrupting substance in aquatic environments. Further research on the mechanisms by which pyrogallol impairs endocrine systems, particularly in fish, is recommended.