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Tris(1,3-dichloro-2-propyl) phosphate (TCPP), a prevalent organophosphorus flame retardant in aquatic environments, has raised significant concerns regarding its ecological risks. This study aims to explore the impacts of TCPP on the reproductive functions of zebrafish and delineate its gender-related toxic mechanisms. By assessing the effects on zebrafish of 10 mg/L TCPP exposure from 30 to 120 days post-fertilization (dpf), we thoroughly evaluated the reproductive capability and endocrine system alterations. Our findings indicated that TCPP exposure disrupted gender differentiation in zebrafish and markedly impaired their reproductive capacity, resulting in decreased egg laying and offspring development quality. Histological analyses of gonadal tissues showed an abnormal increase in immature oocytes in females and a reduction in mature sperm count and spermatogonial structure integrity in males, collectively leading to compromised embryo quality. Additionally, molecular docking results indicated that TCPP showed a strong affinity for estrogen receptors, and TCPP-treated zebrafish exhibited imbalanced sex hormones and increased estrogen receptor expression. Alterations in genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and activation of the steroidogenesis pathway suggested that TCPP targets the HPG axis to regulate sex hormone homeostasis. Tamoxifen (TAM), as a competitive inhibitor of estrogen, exhibited a biphasic effect, as evidenced by the counteraction of TCPP-induced effects in both male and female zebrafish after TAM addition. Overall, our study underscored the gender-dependent reproductive toxicity of TCPP exposure in zebrafish, characterized by diminished reproductive capacity and hormonal disturbances, likely due to interference in the HPG axis and steroidogenesis pathways. These findings emphasize the critical need to consider gender differences in chemical risk assessments for ecosystems and highlight the importance of understanding the mechanisms underlying the effects of chemical pollutants on the reproductive health of aquatic species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infertility has gradually become a global health concern, and evidence suggests that exposure to environmental endocrine-disrupting chemicals (EDCs) represent one of the key causes of infertility. Benzo(a)pyrene (BaP) is a typical EDC that is widespread in the environment. Previous studies have detected BaP in human urine, semen, cervical mucus, oocytes and follicular fluid, resulting in reduced fertility and irreversible reproductive damage. However, the mechanisms underlying the effects of gestational BaP exposure on offspring fertility in male mice have not been fully explored. In this study, pregnant mice were administered BaP at doses of 0, 5, 10 and 20 mg/kg/day via gavage from Days 7.5 to 12.5 of gestation. The results revealed that BaP exposure during pregnancy disrupted the structural integrity of testicular tissue, causing a disorganized arrangement of spermatogenic cells, compromised sperm quality, elevated levels of histone modifications and increased apoptosis in the testicular tissue of F1 male mice. Furthermore, oxidative stress was also increased in the testicular tissue of F1 male mice. BaP activated the AhR/ERα signaling pathway, affected H3K4me3 expression and induced apoptosis in testicular tissue. AhR and Cyp1a1 were overexpressed, and the expression of key molecules in the antioxidant pathway, including Keap1 and Nrf2, was reduced. The combined effects of these molecules led to apoptosis in testicular tissues, damaging and compromising sperm quality. This impairment in testicular cells further contributed to compromised testicular tissues, ultimately impacting the reproductive health of F1 male mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bromo-DragonFLY is a synthetic new psychoactive substance (NPS) that has gained attention due to its powerful and long-lasting hallucinogenic effects, legal status, and widespread availability. This study aimed to use various in silico toxicology methods to predict key toxicological parameters for Bromo-DragonFLY, including acute toxicity (LD 50 ), genotoxicity, cardiotoxicity, health effects, and the potential for endocrine disruption. The results indicate significant acute toxicity with noticeable variations across different species, a low likelihood of genotoxic potential suggesting potential DNA damage, and a notable risk of cardiotoxicity associated with inhibition of the hERG channel. Evaluation of endocrine disruption suggests a low probability of Bromo-DragonFLY interacting with the estrogen receptor α (ER-α), indicating minimal estrogenic activity. These insights from in silico investigations are important for advancing our understanding of this NPS in forensic and clinical toxicology. These initial toxicological examinations establish a foundation for future research efforts and contribute to developing risk assessment and management strategies for using and misusing NPS.

Background: Bisphenol S (BPS) is the main substitute for bisphenol A (BPA), a well-known plasticiser and endocrine disruptor. BPS disrupts ovarian function in several species. Moreover, a few studies have reported that the effects of BPS might be modulated by the metabolic status, and none have characterised the granulosa cell (GC) proteome after chronic BPS exposure., Objectives: This study aimed to decipher the mechanisms of action of chronic BPS exposure on the proteome of ewe GCs while considering the interaction between a deliberate contrasted metabolism and reproductive function., Methods: Forty ewes were split into two groups with contrasted diets: restricted (R, n = 20) and well-fed (WF, n = 20). The R and WF ewes were subdivided according to the dose of BPS administered through the diet (0-50 µg/kg/day), forming four groups: R0, R50, WF0 and WF50. After 3-month BPS daily exposure, GCs were recovered during the pre-ovulatory stage and proteins were analysed by nano-liquid chromatography coupled with tandem mass spectrometry., Results: Chronic exposure to BPS affected the GC proteome differently according to the ewe metabolic status. Fifty-nine out of 958 quantified proteins were differentially abundant between groups and are mainly involved in carbohydrate and lipid pathways. Unsupervised hierarchical clustering of differentially abundant proteins (DAPs) identified four clusters of 34, 6, 5 and 14 proteins according to the BPS exposure and diet interaction. Pairwise comparisons between groups also revealed a strong effect of BPS exposure and diet interaction. Functional analysis of DAPs highlighted that BPS upregulated β-glucuronidase (GUSB; p = 0.002), a protein especially able to deconjugate bisphenol glucuronides (BP-g). Moreover, among unexposed ewes, GUSB was detected only in well-fed ewes., Discussion: Conjugation of glucuronides inhibits the oestrogenic activity of bisphenols. Upregulation of GUSB in ewes dosed with BPS would prolong the oestrogenic effects of BPS by deconjugating BPS-g into free BPS. In addition, literature has reported an up-regulation of GUSB in people suffering from obesity. Therefore, people suffering from obesity could be subjected to prolonged and aggravated exposure to BPS. These data highlighted the deleterious effects of BPS and its interaction with metabolic status., Competing Interests: Declarations Ethical approval and consent to participate All experimental procedures were conducted in accordance with the European Directive 2010/63/EU on the protection of animals used for scientific purposes and approved by the French Ministry of Nation Education, Higher Education, Research and Innovation after ethical assessment by the local ethics committee Comité d’Ethique en Expérimentation Animale Val de Loire (CEEA VdL) and INRAE consented to use the animals in this experimental protocol (protocols registered under APAFIS numbers 13965-2018042008519239v2 and 14014-2018030717477406v2). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Bisphenol A (BPA) exposure is linked to multiple adverse health outcomes, prompting the rise of "BPA-free" products. However, substitutes like Bisphenol S (BPS) and Bisphenol F (BPF) are equally prevalent, with detection frequencies and concentrations rivaling BPA. Our research previously identified BPA as an endocrine disruptor affecting reproductive and developmental systems. This study explores the impact of BPA, BPS, and BPF on endometrial decidualization and receptivity. We detected these bisphenols in serum samples from infertile women undergoing assisted reproductive technology (ART) treatment whose average age was 31.58 years. Human endometrial stromal cells were exposed to varying concentrations (0, 1 nM, 10 nM, 100 nM, and 1 µM) of BPA, BPS, and BPF, following hormonal induction of decidualization (10 nM E2 (Estradiol) + 0.5 mM cAMP (Cyclic adenosine monophosphate) + 1 µM MPA (Medroxyprogesterone acetate) for 6 days). Methods including CCK-8, RT-qPCR, untargeted metabolomics, and transcriptome sequencing assessed cell proliferation, molecular markers, gene expression, and metabolites. BPS levels in the serum of infertile patients were significantly higher than BPA (14.52 vs. 2.58 ng/mL) and even more pronounced in the recurrent implantation failure (RIF) group compared to the Control group (23.46 vs. 5.57 ng/mL). Findings revealed that BPA and its substitutes inhibited endometrial stromal cell proliferation and reduced decidualization markers. Differential metabolites (25, 66, 104) and gene expressions (3260, 9686, 10357) were observed with BPA, BPF, and BPS exposure, respectively. Enriched pathways included glutathione metabolism, arginine biosynthesis, ABC transporters, cAMP signaling, and glucagon signaling. Metabolomics and transcriptome analyses unveiled the reproductive toxic effects of BPA and its substitutes, suggesting significant impacts on endometrial decidualization through diverse signaling pathways., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict interest. We declare that submitted manuscript does not contain previously published material, and is not under consideration for publication elsewhere. The manuscript is truthful original work without fabrication, fraud or plagiarism. Each author has made an important scientific contribution to the study and is thoroughly familiar with the primary data. All authors listed have read the complete manuscript and have approved submission of the paper. All authors declare that there is no conflict interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is a widespread endocrine disruptor that mimics estrogen. The accumulation of BPA within the human body has been shown to be detrimental to ovarian function. However, few studies have focused on the specific mechanisms by which it causes harm to granulosa cells (GCs), pivotal ovarian cells that are responsible for the growth and function of oocytes. In vitro research was conducted using human GC lines (KGN cells). The cells were exposed to various concentrations of BPA (0.1, 1, 10, or 100 µM) for either 24 or 48 hours. Here, our findings indicate that 100 μM BPA inhibits KGN cell proliferation and promotes cell autophagy through inhibiting the PI3K/Akt/mTOR pathway. Interestingly, these effects could be partly reversed by an NTRK2 activator (LM22b-10). NTRK2 is the receptor for BDNF. Moreover, via the use of bioinformatics tools, miR-204 was predicted to target BDNF. Additionally, our findings confirmed that miR-204 has the ability to directly target BDNF through a luciferase assay. Downregulation of miR-204 abrogated the BPA exposure-mediated effects on proliferation and autophagy. Furthermore, the inhibition of miR-204 significantly reversed the downregulation of PI3K/Akt/mTOR pathway-related molecules. Similarly, we validated miR-204 as a novel miRNA involved in BPA-mediated damage to GC proliferation and autophagy, and our data provide the first in vitro evidence that increasing miR-204 expression and inhibiting the BDNF/NTRK2-mediated PI3K/Akt/mTOR signaling pathway are involved in the BPA-induced toxic effects in KGN cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alkylphenols (APs) may cause gestational diabetes mellitus (GDM) in pregnant women by impairing glucose metabolism through endocrine disruption. However, the current literature has limited epidemiological evidence on the association between APs exposure and the risk of GDM, especially the lack of evidence on joint exposure. Thus, we evaluated the effect of exposure to APs during early pregnancy on the risk of GDM. The study involved 2035 pregnant women from Guangxi Zhuang Birth Cohort (GZBC) in China. Poisson regression model, restricted cubic spline (RCS), Bayesian kernel machine regression (BKMR), and quantile g-computation (Qgcomp) were conducted to evaluate the effects of serum APs levels on the risk of GDM in pregnant women. For each Ln-unit increase in the serum nonylphenol (NP) of pregnant women, the adjusted relative risk (RR) for GDM risk was 1.12 (95 % CI: 1.00, 1.24). After sex stratification, the effect was more pronounced among pregnant women carrying female fetuses（RR=1.22; 95 % CI: 1.09, 1.38). The serum 4-t-octylphenol (4-T-OP) of the medium-exposure (adjusted RR = 3.25: 95 % CI: 1.30, 8.12) and high-exposure groups (adjusted RR = 2.90: 95 % CI: 1.15, 7.31) were related to a significantly increased risk of GDM in pregnant women carrying female fetuses only when compared to the low-exposure group. A reverse U-shaped nonlinear association was found between 4-n-octylphenol (4-N-OP) and 4-n-nonylphenol (4-N-NP) concentrations and GDM risk, and it was more susceptible in pregnant women carrying female fetuses. The Qgcomp and BKMR models showed that exposure to APs mixtures was correlated with an elevated risk of GDM in pregnant women carrying female fetuses (adjusted OR = 1.90: 95 % CI: 1.07, 3.38). Exposure to APs during early pregnancy may have potential fetal sex-specific effects on the risk of GDM, with pregnant women carrying female fetuses being more susceptible., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), or 3,3',5,5'-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The corresponding author, Alexander Suvorov, is a cofounder and CEO of the biotechnology startup ReGENE LLC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bisphenol A (BPA), a widely used chemical in the production of plastics and epoxy resins, has garnered significant attention due to its association with adverse health effects, particularly its endocrine-disrupting properties. Regulatory measures aimed at reducing human exposure to BPA have led to a proliferation of alternative chemicals used in various consumer and industrial products. While these alternatives serve to reduce BPA exposure, concerns have arisen regarding their safety and potential toxicity as regrettable substitutes. Previous efforts have demonstrated that in vitro high-throughput transcriptomics (HTTr) studies can be used to assess the endocrine-disrupting potential of BPA alternatives, and this strategy produces transcriptomic points-of-departure (tPODs) that are protective of human health when compared to the PODs from traditional rodent studies. In this study, we used in vitro HTTr to assess the potential for toxicity of eleven data-poor legacy chemicals sharing structural similarities to BPA. Human breast cancer MCF-7 cells were exposed to BPA and 11 alternatives at concentrations ranging from 0.1 to 25 μM to assess toxicity. Analysis of global transcriptomic changes and a previously characterized estrogen receptor alpha (ERα) transcriptomic biomarker signature revealed that 9 of 11 chemicals altered gene expression relative to controls. One of the chemicals (2,4'-Bisphenol A) activated the ERα biomarker at the same concentration as BPA (i.e., 4,4'-BPA) but was deemed to be more potent as it induced global transcriptomic changes at lower concentrations. These results address data gaps in support of ongoing screening assessments to identify BPA alternatives with hazard potential and help to identify potential candidates that may serve as safer alternatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Environmental phenols were recognized as endocrine disrupting chemicals (EDCs). However, their impact on childhood anthropometric measures and blood pressure (BP) is still inconclusive. Limited studies have simultaneously considered prenatal and childhood exposures in analyzing mixtures of phenols., Objective: We investigated the relationships between combined prenatal and childhood exposures (two periodic exposures) to phenol mixtures and anthropometric measure and BP, to further identify the vulnerable periods of phenol exposure and to explore the important individual contribution of each phenol., Methods: We analyzed 434 mother-child dyads from the Sheyang Mini Birth Cohort Study (SMBCS). The urinary concentrations of 11 phenolic compounds were measured using gas chromatography tandem mass spectrometry. Generalized linear regression models (GLMs) and hierarchical Bayesian Kernel Machine Regression (hBKMR) were used to examine the effects of individual phenolic compounds at each period and of two periodic exposures., Results: In the single-chemical analysis, prenatal or childhood exposure to specific phenols, especially Benzopheone-3 (BP3), 4-tert-Octylphenol (4-tOP), and Benzyl paraben (BePB) were associated with BMI z-scores (BAZ), Waist-to-height ratio (WHtR), and BP. In the hBKMR models, two periodic exposures to phenol mixtures had a U-shaped association with WHtR, primarily driven by childhood BePB exposure. Moreover, among the phenol mixtures analysis, childhood 4-tOP exposure was identified as the primary contributor to the positive association with diastolic BP. Concurrent exposure to phenol mixtures resulted in greater susceptibility., Conclusions: We found that prenatal and childhood exposure to phenol mixtures might influence childhood obesity and elevate blood pressure levels. Concurrent exposure to 4-tOP may be the primary driver of the positive associations with BP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zhijun Zhou reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Zearalenone (ZEN), an endocrine-disrupting mycotoxin, is prevalent and persists in the environment. ZEN has the potential to cause adverse health impacts extending over generations, yet there is a lack of relevant research. Therefore, we explored the ZEN-induced multi-/trans-generational locomotive and reproductive toxicities, as well as the underlying epigenetic mechanisms in Caenorhabditis elegans. In multi-generational analysis, the evolution tendency and toxicity latency were observed under sustained exposure to 0.1 and 1 μM ZEN across five generations (P0-F4). The toxic effects were found in filial generations even if the initial parental exposure showed no apparent effects. Trans-generational results indicated the toxic inheritance phenomenon of 10 and 50 μM ZEN, where a single generation of ZEN exposure was sufficient to affect subsequent generations (F1-F3). Additionally, the pattern of locomotion was relatively sensitive in both generational studies, indicating varying sensitivity between indicators. Regarding epigenetic mechanism of toxicity transmission, ZEN significantly decreased the parental expression of histone methyltransferase encoded genes set-2, mes-2, and mes-4. Notably, the downregulation of mes-4 persisted in the unexposed F1 and F2 generations under trans-generational exposure. Furthermore, the mes-4 binding and reproduction-related rme-2 also decreased across generations. Moreover, parental germline specific knockdown of mes-4 eliminated the inherited locomotive and reproductive toxic effects in offspring, showing that mes-4 acted as transmitter in ZEN-induced generational toxicities. These findings suggest that ZEN is an epigenetic environmental pollutant, with a possible genetic biomarker mes-4 mediating the germline dependent transmission of ZEN-triggered toxicity over generations. This study provides significant insights into ZEN-induced epigenotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tolylfluanid is a widely used pesticide and antifouling agent in agricultural and marine industries and is recognized as a potential endocrine disruptor. However, the toxicological effects of tolylfluanid on the placenta development was not elucidated. This study used trophoblastic cell (HTR-8/SVneo cell) and endometrial cell (T HESCs) lines as in vitro model and mouse models as in vivo model to investigate the toxic effects of tolylfluanid on implantation-associated cell and placenta development during early pregnancy. Experimental results indicated that both cell lines exhibited reduced viability upon tolylfluanid exposure. Various in vitro experiments were conducted at <1 mg/L concentration. The results indicate that tolylfluanid can arrest cell cycle and induce apoptosis in endometrial and trophoblastic cells, abnormally regulate Ca 2+ homeostasis and MAPK signaling pathways, and disrupt mitochondrial function. In vivo experiments, subchronic tolylfluanid exposure to mouse during puberty and pregnancy period impaired placenta development, resulting in reduced fetal and placental weight, abnormal placental structures, and altered gene expression. Specifically, a decrease in the ratio of labyrinth/junctional zones and changes in placenta gene expression patterns after tolylfluanid exposure were similar to characters of adverse pregnancy outcomes such as preeclampsia and fetal growth restriction (FGR). This study suggests that tolylfluanid exposure may have negative outcomes on female reproduction, and highlights the need for stricter regulation and monitoring of tolylfluanid use to protect women's reproductive health. This is the first study indicating the adverse effects of tolylfluanid on implantation and placental development during pregnancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In recent years, the use of endocrine-disrupting chemicals (EDCs) has become increasingly common, leading to severe environmental pollution and harm to aquatic organisms. 17α-Methyltestosterone (MT) is a synthetic androgen that can cause immunotoxicity in aquaculture, affecting fish health. To address this issue, this study aimed to investigate the effect of Vitamin C (VC) on MT-induced immunotoxicity and determine the optimal VC supplementation., Results: Carassius auratus was exposed to 50 ng/L MT and treated with 25, 50, and 150 mg/kg VC for 7, 14, and 21 d. Morphological indicators, histological characteristics, hepatic antioxidant capacity, and immune-related gene expression were analyzed. Additionally, RNA-seq was performed on the liver tissues of the control, MT, and MT + 25 mg/kg VC groups after 21 d. Results showed that, MT treatment significantly increased liver malondialdehyde content and inhibited immune-related gene expression (TNF-α, IL-8, INF-γ, IL-10, Caspase-9, and IGF-I), causing oxidative stress and immunotoxicity, leading to hepatic steatosis. However, supplementation with 25-50 mg/kg VC effectively alleviated the MT-induced damage to the hepatic structure and immune system. RNA-seq revealed significant enrichment of differentially expressed genes in multiple signaling pathways, including the mTOR, MAPK, and Wnt pathways., Conclusions: In summary, 25-50 mg/kg VC alleviated inhibitory effect of MT on immune-related genes in C. auratus liver, reducing MT-induced tissue damage. VC not only alleviated inflammation, oxidative stress, and immunotoxicity induced by MT through the regulation of the mTOR, MAPK, and Wnt signaling pathways, but also indirectly enhanced cellular antioxidant defense mechanisms by regulating the NRF2 pathway. This provides a theoretical basis for VC application in aquaculture, improving fish health and increasing efficiency., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Animal Protection and Ethics Committee of Shanxi Agricultural University, approval number IACUC No. SXAU-EAW-2018G.R.0201. Throughout the experiment, all fish were anesthetized with MS-222 (1: 10,000) to minimize suffering as much as possible. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Euthanasia and anesthesia methods MS-222 is a widely used anesthetic for aquatic animals, particularly in experimental research and euthanasia procedures that prioritize animal welfare. MS-222 effectively alleviates pain and stress in fish during experimental processes. When using MS-222 for anesthesia, it is first diluted to the recommended concentration (typically 25–30 g/m³) and then added to water that has been aerated for 24 h. The fish are immersed in this solution for 15–20 min, with observation until the desired anesthetic effect is achieved., (© 2024. The Author(s).)

Because of its ubiquitous occurrence in the environment, decabromodiphenyl ethane (DBDPE), a novel brominated flame retardant, has been widely concerned. However, its transgenerational thyroid disrupting potential and intricate mechanism are barely explored. Therefore, zebrafish embryos were exposed to environmentally relevant concentrations of DBDPE (0, 0.1, 1 and 10 nM) until sexual maturity. The results indicated that life-time exposure to DBDPE caused anxiety-like behavior in unexposed offspring. Furthermore, the changing of thyroid hormones as well as transcriptional and DNA methylation level in the promoter region of related genes were evaluated. The thyroid disruptions observed in F1 larvae were primarily attributed to excessive transfer of thyroid hormone from F0 adults to F1 eggs. Conversely, the disruptions in F2 larvae were likely due to inherited epigenetic changes, specifically hypomethylation of crh and hypermethylation of ugt1ab, passed down from the F1 generation. Additionally, our results revealed sex-specific responses of the hypothalamic-pituitary-thyroid (HPT) axis in adult zebrafish. Furthermore, thyroid disruptions observed in unexposed offspring were more likely inherited from their mothers. The current results prompted our in-depth understanding of the multi- and transgenerational toxicity by DBDPE, and also highlighted the need to consider their adverse effects on persistent and inheritable epigenetic changes in future research on emerging pollutants., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The widespread use of chiral triazole fungicide cyproconazole (CPZ) in agricultural fields has led to frequent detection of CPZ in the environment. The restriction of CPZ in the EU raised wide concerns regarding its potential endocrine-disrupting effects (EDEs). The present study was conducted to evaluate EDEs of CPZ stereoisomers in vitro , in silico , and in vivo . The reporter gene assay indicated that all CPZ stereoisomers were agonists to the human estrogenic receptor α. (2 S ,3 S )-(+)- and (2 R ,3 S )-(-)-CPZ exhibited stronger binding capacities to ERα compared with (2 R ,3 R )-(-)- and (2 S ,3 R )-(+)-CPZ. Our computational studies showed consistent results with reporter gene assay, elucidating the stereoselective binding mode of CPZ to estrogen receptor. In zebrafish embryos, the 96h-lethality of CPZ stereoisomers ordered (2 R ,3 R )-(-)- > (2 R ,3 S )-(-)- > (2 S ,3 S )-(+)- > Rac- > (2 S ,3 R )-(+)-CPZ. Stereoselective developmental toxicity of CPZ was observed while (2 R ,3 S )-(-)-CPZ is the most toxic isomer. The estrogenic hormones were significantly decreased in (2 S ,3 R )-(+)- and (2 R ,3 S )-(-)-CPZ groups and enhanced in (2 S ,3 S )-(+)- and (2 R ,3 R )-(-)-CPZ, along with the gene expression in hypothalamic-pituitary-gonad axis altered. CPZ shows no thyroid hormone activity. These data clarified that CPZ is a new-found endocrine disruptor threatening human health and each stereoisomer of CPZ showed stereoselective EDEs by regulating the nuclear receptor-mediated gene expression.

Salicylate preservatives are widely used in consumer products and pharmaceuticals. This study investigates their potential endocrine-disrupting effects on neurosteroidogenesis, focusing on 5α-reductase type 1 (SRD5A1). We evaluated the effects of 13 salicylates on human SRD5A1 using SF126 glioblastoma cell microsomes and rat brain microsomes, examining dihydrotestosterone production in SF126 cells. Results revealed a hierarchy of inhibitory potency against human SRD5A1, with methyl salicylate (IC 50 , 71.93 μM) to menthyl salicylate (2.41 μM), indicating increasing potency. Kinetic analysis indicates their mixed/noncompetitive inhibitions. In SF126 cells, all salicylates at 100 μM significantly reduced dihydrotestosterone production. Rat SRD5A1 showed reduced sensitivity, with menthyl salicylate as the most potent inhibitor (IC 50 , 17.12 μM). Docking analysis suggests salicylates bind to the reduced nicotinamide adenine dinucleotide phosphate site of both human and rat SRD5A1. Bivariate correlation analysis highlights the influence of LogP, molecular weight, carbon number in the alcohol moiety, and p K a on inhibitory potency. 3D-QSAR revealed the importance of hydrophobic aromatic regions in SRD5A1 binding. This study delineates the inhibitory effects of salicylates and binding mechanisms on human and rat SRD5A1, providing insights into their impact on neurosteroid production.

Bisphenols (BPs) are recognized as endocrine disrupting compounds and have garnered increasing attention due to their widespread utilization. However, the varying biological toxicities and underlying mechanisms of BPs with different functional groups remain unknown. In the present study, the toxic effects of four BPs (BPA, BPS, BPAF, and TBBPA) on a photosynthetic microalgae Chromochloris zofingiensis were compared. Results showed that halogen-containing BPs exhibited higher cellular uptake, leading to more severe oxidative stress, lower photosynthetic efficiency, and greater accumulation of starch and lipids. Specifically, TBBPA with bromine groups showed a greater toxicity than BPAF with fluorine groups, possibly due to the incomplete debromination in C. zofingiensis. Transcriptomic analysis revealed that halogen-containing BPs triggered greater number of differentially expressed genes (DEGs), and only 64 common DEGs were found among different BPs, indicating that the effects of BPs with different functional groups varied greatly. Genes involved in endocytosis, peroxisomes, and endoplasmic reticulum protein processing pathways were mostly upregulated across different BPs, while photosynthesis-related genes showed varied expression, possibly due to their distinct functional groups. Additionally, SIN3A, ZFP36L, CHMP, and ATF2 emerged as potential key regulatory genes. Overall, this study thoroughly explained how functional groups impact the toxicity and biodegradation of BPs in C. zofingiensis., Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zuzic Lorena reports equipment, drugs, or supplies was provided by Novo Nordisk Foundation. Zuzic Lorena reports financial support was provided by Lundbeck Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bisphenol A (BPA), a known endocrine disruptor, is ubiquitous in various aquatic environments. Appendicularians are among the most abundant mesozooplankton populations and occupy a crucial niche in marine ecosystems. However, no toxicological data are available concerning the effects of BPA on this functional group. In this study, an evaluation of the toxicity of environmentally relevant levels of BPA (2.5-150 μg/L) on the appendicularian Oikopleura dioica, including its morphology and transcriptome, was conducted. Our results demonstrated the high sensitivity of O. dioica to BPA, with a LC 50 of 142 μg/L. Exposure to 125 μg/L BPA significantly inhibited the somatic growth, gonadal development and reproduction of individuals, whereas exposure to an environmentally safe concentration (2.5 μg/L) affected female fecundity and fitness as well as male gene expression. The results of the transcriptomic analysis suggest that males were more sensitive to BPA stress at the molecular level. BPA exposure not only led to abnormal secretion of digestive enzymes and phospholipase A2, affecting the function of the digestive system and arachidonic acid but also significantly down-regulated the expression of mRNAs related to enzymes involved in carbohydrate and energy metabolism in males. These findings suggest that the current safe environmental concentrations may not be safe., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shuai Li reports financial support was provided by National Natural Science Foundation of China. Yi Liang reports financial support was provided by Shandong Provincial Natural Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The toxicity of microplastics (MPs) to aquatic animals is closely related to the presence and release kinetics of contained additives, as most plastic products contain various additives. However, the relationship between the occurrence and release of additives from MPs, and their individual or combined toxicity remains unclear. In this study, the nanoscale distribution and release of tetrabromobisphenol A (TBBPA, a common flame retardant with endocrine-disrupting effect) in polystyrene (PS) MPs, and the long-term (60 days) toxicity of TBBPA and MPs containing TBBPA (at doses of 0 %, 1 %, 10 %, w/w) to Xenopus tropicalis tadpoles were investigated. Exposure to 10 μg/L TBBPA alone was the most toxics, while the encapsulation of TBBPA in MPs significantly delayed its lethal toxicity to tadpoles by inhibiting the rapid and extensive release of TBBPA. PS MPs alone and MPs containing 10 % TBBPA exhibited delayed survival toxicity compared to TBBPA alone, whereas PS MPs containing 1 % TBBPA did not show this effect but inhibited growth. These findings suggest that chronic toxicity assessments should be based on long-term (months or even years) exposure experiments due to the encapsulation-controlled slow release of toxic additives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spermatogenesis starts with the onset of puberty within the seminiferous epithelium of the testes. It is a complex process under intricate control of the endocrine system. Physiological regulations by steroid hormones in general and by estrogens in particular are due to their chemical nature prone to be disrupted by exogenous factors acting as endocrine disruptors (EDs). 17α-Ethynylestradiol (EE2) is an environmental pollutant with a confirmed ED activity and a well-known effect on spermatogenesis and chromatin remodeling in haploid germ cells. The aim of our study was to assess possible effects of two doses (2.5ng/ml; 2.5 μg/ml) of EE2 on both histone-to-protamine exchange and epigenetic profiles during spermatogenesis performing a multi/transgenerational study in mice. Our results demonstrated an impaired histone-to-protamine exchange with a significantly higher histone retention in sperm nuclei of exposed animals, when this process was accompanied by the changes of histone post-translational modifications (PTMs) abundancies with a prominent effect on H3K9Ac and partial changes in protamine 1 promoter methylation status. Furthermore, individual changes in molecular phenotypes were partially transmitted to subsequent generations, when no direct trans-generational effect was observed. Finally, the uncovered specific localization of the histone retention in sperm nuclei and their specific PTMs profile after EE2 exposure may indicate an estrogenic effect on sperm motility and early embryonic development via epigenetic mechanisms., (© 2024. The Author(s).)

Background: Inhalation is a major pathway for phthalates (PAEs), an endocrine disruptor, to enter the human body. The actual internal exposure amount that participates in metabolism cannot be estimated by calculating total inhalation intake., Objective: To estimate the accumulation in each region of the respiratory tract after long-term exposure to PAEs in different populations., Methods: A mass transfer model was developed to simulate the long-term accumulation of PAEs in respiratory tract through inhalation. The model considered (1) mass transfer of PAEs in three phases across seven regions, (2) the effect of temperature differences on the mass transfer process. Based on this model, we simulated adult exposure to PAEs in a laboratory, identified key model parameters, and further simulated various scenarios for children, adults, and elders., Results: PAEs are not completely cleared from the respiratory tract after 16 hours, following 8 hours of daily exposure. Under regular laboratory environment, accumulation after 30 days is 3.8 times higher than that after the first day. The distribution of PAEs between the gas and mucus phases has a greater impact on the results than between the gas and particle phases. Children are at the highest risk to Diethyl phthalate (DEP) exposure compared with adults and elders. Nearly 80 % of DEP is exhaled, with 14 % accumulating in the alveolar region after an hour., Conclusion: This model links indoor air PAEs to human internal exposure, showing that most PAEs are exhaled, while the remainder accumulates in the respiratory tract and may participate in human metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As an alternative to perfluorooctane sulfonate, sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has been widely used and caused ubiquitous water pollution. However, its toxicity to aquatic organisms is still not well known. Therefore, in this study, parental zebrafish were exposed to OBS at environmentally relevant concentrations from ∼ 2 h post-fertilization to 21 days post-fertilization (dpf) in order to investigate the thyroid disrupting effects in F0 adults and F1 offspring. Histopathological changes, such as hyperplasia of thyroid follicular epithelia and colloidal depletion, were observed in F0 adults at 180 dpf. In F0 females, thyroxine (T4) levels were significantly reduced in 30 and 300 μg/L exposure groups, while triiodothyronine (T3) levels were significantly increased in 3 μg/L exposure group. For F0 males, significant increases of T4 and T3 levels were observed, revealing the sex-specific differences after the OBS exposure. The transcription levels of some key genes related to the hypothalamic-pituitary-thyroid (HPT) axis were significantly disrupted, which induced the thyroid endocrine disruption effects in adult zebrafish even after a prolonged recovery period. For F1 offspring, the thyroid hormone (TH) homeostasis was also altered as T4 and T3 levels in embryos/larvae exhibited similar changes as F0 females. The transcription levels of some key genes related to the HPT axis were also significantly dysregulated, suggesting the transgenerational thyroid disrupting effects of OBS in F1 offspring. In addition, the decreased swirl-escape rate was observed in F1 larvae, which could be caused by disrupting gene expressions related to the central nervous system development and be associated with the TH dyshomeostasis. Therefore, parental OBS exposure at early life stage resulted in thyroid endocrine disruption effects in both F0 adult zebrafish and F1 offspring, and caused the developmental neurotoxicity in F1 larvae., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Homosalate (HS) and octisalate (OS), which are used in sunscreen for the purpose of blocking ultraviolet rays, are frequently detected in water environment. Although effects on estrogens and androgens have been reported, studies on thyroid and growth hormone endocrine disruption are limited. In the present study, larval mortality was compared in wild-type and two knockout fish (thyroid hormone receptor alpha a knockout (thrαa -/- ) and dre-miR-499 knockout (dre-miR-499 -/- )) after 96 h of exposure to HS and OS (0, 0.003, 0.03, 0.3, 3, 30 and 300 µg/L). To investigate the mechanisms of thyroid and growth hormone endocrine disruption, we measured the levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1), and the regulation of representative genes related to the hypothalamus-pituitary-thyroid (HPT) and GH/IGF axis in wild-type zebrafish exposed to target chemicals. The significantly lower larval survival rate of thrαa -/- and dre-miR-499 -/- fish exposed to 300 μg/L of HS and OS suggest that thyroid hormone receptors and dre-miR-499 play a crucial role in the toxic effects of HS and OS. The finding of a significant increase in T3 and T4 in zebrafish larvae exposed to HS and OS supports a significant decrease in the crh gene. The reduction of GH and IGF-1 in fish exposed to HS and OS is well supported by the regulation of genes involved in the GH/IGF axis. Our observations suggest that exposure to HS and OS affects not only thyroid hormone receptors and their associated miRNAs, but also the feedback routes of HPT and GH/IGF axes, ultimately leading to growth reduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-persistent endocrine-disrupting chemicals (EDCs) are of significant concern due to their reproductive toxicity. Previous research reported a relationship between a single type of EDCs and endometriosis. Yet, evidence regarding mixed exposure of multiple categories of EDCs is scarce. Between 2014 and 2018, our hospital-based case-control study recruited 238 endometriosis cases diagnosed by laparoscopy and 296 normal controls in China. Seventeen non-persistent EDCs (phthalates and bisphenols) were measured in urine. The association of single EDC with endometriosis was estimated using logistic regression, while the association between EDC mixture and endometriosis was modeled by Bayesian kernel machine regression (BKMR), quantile-based g-computation (q-gcomp), and principal component analysis (PCA). Consistent results were observed in both single and mixture models where phthalates and bisphenols were associated with increased risk of endometriosis (mixture effect: adjusted odds ratio (aOR)=1.44, 1.22-1.70) and the major contributors were bisphenol A (BPA) and the metabolites of di(2-ethylhexyl) phthalate (DEHP). Interaction analysis showed that bisphenols exhibited significant synergistic interactions with phthalates. Our results suggest that non-persistent EDCs are associated with endometriosis but the underlying mechanisms remain to be elucidated. Our finding may have important public health implications in preventing endometriosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Question: Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles?, Summary Answer: Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later., What Is Known Already: Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction., Study Design, Size, Duration: This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother-Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002., Participants/materials, Setting, Methods: A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females., Main Results and the Role of Chance: In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration., Limitations, Reasons for Caution: Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited., Wider Implications of the Findings: Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system., Study Funding/competing Interest(s): The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Osteoporosis (OP), a metabolic disorder predominantly impacting postmenopausal women, has seen considerable progress in diagnosis and treatment over the past few decades. However, the intricate interplay between genetic factors and endocrine disruptors (EDCs) in the pathogenesis of OP remains inadequately elucidated. The objective of this research is to examine the environmental pollutants and their regulatory mechanisms that could potentially influence the pathogenesis of OP, in order to establish a theoretical foundation for the targeted prevention and medical management of individuals with OP. Utilizing CTD and GEO datasets, network toxicology and bioinformatics analyses were conducted to identify target genes from a pool of 98 co-associated genes. Subsequently, a novel prediction model was developed employing a multiple machine learning algorithm. The efficacy of the model was validated based on the area under the receiver operating characteristic curve. Finally, real-time quantitative polymerase chain reaction (qRT-PCR) was used to confirm the expression levels of key genes in clinical samples. We have identified significant genes (FOXO3 and LUM) associated with OP and conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, immune infiltration analysis, and molecular docking analysis. Through the analysis of these key genes, we have identified 13 EDCs that have the potential to impact OP. Several endocrine disruptors, such as Dexamethasone, Perfluorononanoic acid, genistein, cadmium, and bisphenol A, have been identified as notable environmental pollutants that impact the OP. Molecular docking analysis revealed significant binding affinity of major EDCs to the post-translational protein structures of key genes. This study demonstrates that EDCs, including dexamethasone, perfluorononanoic acid, genistein, cadmium, and bisphenol A, can be identified as important environmental pollutants affecting OP, and that FOXO3 and LUM have the potential to be diagnostic markers for OP. These results elucidate a novel association between EDCs regulated by key genes and the onset of OP., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Bisphenol A (BPA) is among the extensively researched environmental endocrine-disrupting chemicals (EDCs), and its utilization is restricted owing to the detrimental impacts it has on human health. Bisphenol AP (BPAP) is one of the alternatives to BPA, but the influence of BPAP on human health has not been elucidated. The objective of the current research was to determine the influence of BPAP exposure on the in vitro maturation of mouse oocytes and to explore its potential reproductive toxicity. BPAP exposure was found to inhibit polar body extrusion during mouse oocyte maturation, resulting in an arrest at the metaphase I stage of meiosis. Exposure to BPAP led to sustained activation of BubR1, preventing the degradation of both Securin and Cyclin B1. Mechanistically, BPAP exposure disrupts spindle assembly and chromosome alignment. Levels of acetylated α-tubulin were significantly elevated in BPAP-treated oocytes, reflecting decreased spindle stability. Exposure to BPAP also induced DNA damage and impaired DNA damage repair. In addition, BPAP exposure altered histone modification levels. In summary, this investigation suggests that exposure to BPAP can influence cytoskeletal assembly, interfere with cell cycle progression, induce DNA damage, alter histone modifications, and ultimately impede oocyte meiotic maturation. This investigation enhances understanding of the impact of bisphenol analogs on female gametes, underscoring that BPAP cannot be considered a reliable replacement for BPA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Bisphenol A (BPA) is a chemical that disrupts the endocrine system and may have negative implications on the lipid metabolism of organisms. To ascertain BPA implications on lipid metabolism in the hepatopancreas of Sesarmops sinensis, we exposed S. sinensis to different concentrations of BPA for 14 days. The outcomes manifested that BPA may stimulate hepatopancreas injury and lipid deposition in the hepatopancreas of S. sinensis and lead to the increase of hepatosomatic index (HSI). Transcriptome analysis showed that lipid metabolism-related pathways were significantly enriched in KEGG pathways. BPA exposure also caused disorders in lipid metabolism by altering fatty acid composition and lipid metabolites. The up-regulation of lipid synthesis genes and the alteration of lipid transport genes may be important reasons for the disorder of lipid metabolism. Furthermore, these outcomes provide a fresh point of reference for comprehending the ecotoxicological impacts of BPA on aquatic organisms., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Progestins are crucial steroid hormones that have attracted wide attention due to their endocrine disrupting effects in fish. The aim of this study is to investigate the effects of long-term exposure to low concentrations of norgestrel (NGT) on the reproductive and thyroid endocrine systems of adult zebrafish. Adult zebrafish were exposed to 7 and 39 ng/L NGT for a duration of 90 days. The results revealed that exposure to 39 ng/L NGT led to a significant up-regulation of 3β-hydroxysteroid dehydrogenase (hsd3b) and 20β-hydroxysteroid dehydrogenase (hsd20b) genes in the ovary of female zebrafish. Additionally, there was a significant up-regulation of 11β-hydroxysteroid dehydrogenase 2 (hsd11b2) gene in the testis of male zebrafish. Furthermore, egg production decreased significantly, accompanied by notable alterations in the proportion of ovarian development stages, as well as reductions of sex hormone levels (E2, 11-KT, and T) in both females and males. However, long-term exposure to low concentrations of NGT did not lead to changes in thyroid hormone levels and thyroid histopathology in adult zebrafish. The overall results imply that environmental concentrations of NGT have a strong endocrine disrupting effect on the reproductive system of zebrafish, while the thyroid system is not sensitive to NGT exposure. The present study underscores the reproductive endocrine impacts of NGT and emphasizes the necessity for prolonged exposure at environmental concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There are many concerns about the impacts of Endocrine-Disrupting Chemicals on both wildlife and human populations. A plethora of chemicals have been shown to interfere with the Hypothalamic-Pituitary-Thyroid (HPT) axis in vertebrates. Disruption of the HPT axis is one of main endocrine criteria considered for the regulation of chemicals, along with the estrogen axis, androgen axis and steroidogenesis (EATS). In response to these concerns, the Organization for Economic Cooperation and Development (OECD) initiated the validation of test guidelines (TGs) covering the EATS modalities. Regarding thyroid activity and/or disruption assessment, three OECD TGs are validated, all of them using amphibians. To date, no OECD TGs based on fish are available for the detection of Thyroid Active Chemicals (TACs). To fill this gap, we developed a new test for the detection of TACs, the TETHYS assay (Transgenic Eleuthero-embryonic THYroid-Specific assay). This assay uses a medaka (Oryzias latipes) transgenic line Tg(tg:eGFP) expressing Green Fluorescent Protein in the thyroid follicles, under the control of the thyroglobulin promoter. This assay is performed at eleuthero-embryonic life-stages with an exposure length of 72 h. In the present study, the following reference chemicals with known thyroid hormone system mechanism of action have been tested: methimazole, sodium perchlorate, sodium tetrafluoroborate, diclofenac, iopanoic acid, sobetirome, NH-3 and 1-850. Except for the thyroid receptor antagonists, all chemicals tested were identified as thyroid active, modifying the total fluorescence and the size of the thyroid follicles. To investigate the test specificity, we tested three chemicals presumed to be inert on the HPT axis: cefuroxime, abamectin and 17α-ethinylestradiol. All were found to be inactive in the TETHYS assay. This promising New Approach Methodology can serve as a foundation for the development of a new OECD TG in the frame of regulatory assessment of chemicals for thyroid activity., Competing Interests: Declaration of competing interest Laurent Sachs reports a relationship with L'Oréal SA that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In this study an impact of norfluoxetine (NFLU) on Mytilus trossulus gonads was investigated focusing on sex-related differences in hormonal changes, gene expression, and transcriptomic profiling. Sex-specific differences in gonadal serotonin levels were found. NFLU stimulates serotonin synthesis and/or transport in female gonads, potentially accelerating oocyte maturation and gamete release. In males, NFLU decreases serotonin level what likely leads to impeding sperm maturation and thus spawning delay. Transcriptomic analyses highlighted the presence of NFLU-induced changes in gene expression related to gametogenesis and neurotransmission. In females, NFLU upregulated genes associated with oocyte development and downregulated those involved in sperm maturation. NFLU-treated males exhibited mixed effects in their genes in relation to spermatogenesis. Additionally, sex-related differences in the expression of the CYP450 genes responsible for detoxification were found. Overall, norfluoxetine acts as an endocrine-disrupting chemical and impacts gonadal serotonin levels and gene expression, potentially disrupting reproductive success of M. trossulus., Competing Interests: Declaration of competing interest All authors declare that they have no know competing financial interest or personal relationships that would influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study investigated the effects of Bisphenol A (BPA), a common endocrine-disrupting chemical, on the antioxidant enzyme activities in the hepatopancreas and the expression of genes related to ovarian development in oriental river prawns (Macrobrachium nipponense). The 24hLC50 and 48hLC50 values for BPA were 80.59 mg/L and 63.90 mg/L, respectively, with a safe concentration of 12.06 mg/L. Prawns were exposed to low (4.85 mg/L), safe (12.06 mg/L), and high (30.00 mg/L) concentrations of BPA for 10 days to measure enzyme activities, and for 20 days followed by 7 days in BPA-free water to measure gene expression. Short-term exposure (12 h, 1d, 3d) to low concentration BPA did not significantly affect superoxide dismutase (SOD) activity in the hepatopancreas (P > 0.05), but long-term exposure (6d, 10d) significantly reduced SOD activity (P < 0.05). Catalase (CAT) activity showed no significant changes throughout the low concentration exposure period (P > 0.05). At safe and high concentrations, SOD and CAT activities significantly decreased after 12 h of exposure (P < 0.05). BPA affected heat shock protein 90 (HSP90) expression in the ovary, with low concentration BPA significantly upregulating HSP90 after 1 day (P < 0.05), but returning to normal levels after 10 and 20 days. At the safe concentration, HSP90 was significantly upregulated at all three sampling points (1d, 10d, 20d) (P < 0.05), while high concentration exposure led to significant upregulation only on day 10 (P < 0.05). Low concentration BPA had no significant effect on Cathepsin B (CB) and Cathepsin L (CL) gene expression in the ovaries (P > 0.05). However, safe concentration exposure promoted CB expression on days 1, 10, and 20 (P < 0.05), while high concentration exposure significantly increased CB expression on day 1 (P < 0.05), with levels returning to normal on days 10 and 20. CL expression significantly increased after 20 days of exposure to both safe and high concentrations (P < 0.05). Gene expression levels in the ovaries returned to normal after transfer to BPA-free water, with HSP90 and CB normalizing by day 1, and CL by day 7. These results indicate that even safe concentrations of BPA impose stress on the hepatopancreas and increase the expression of HSP90, CB, and CL genes in the ovaries, affecting ovarian development. And, these effects are reversible within a certain period after the removal of BPA., Competing Interests: Declaration of competing interest The authors declare that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2024. Published by Elsevier B.V.)

Bisphenols are mainly used as protective coatings for plastics and resin-based materials in various consumer products. Industrial producers have a high demand for bisphenol A (BPA) among all bisphenol substitutes for various consumer products. However, according to reports, prolonged exposure to BPA can cause multiple health issues, including neurodevelopmental disorders in young children. BPA exposure during pregnancy has been considered as the primary cause of increasing the risk of neurological disorders in children as their neural systems are designed to respond to any environmental changes during prenatal life. Recently, there has been an increased focus on the effects of prenatal exposure to BPA, as it has been found to alter gene expression related to epigenetic mechanisms like DNA methylation, histone modification, and microRNA expression. Based on the evidence, frequent interactions can lead to inherited changes in an individual's neural profile. In this review, we delve into the current knowledge regarding the toxicity mechanism of BPA for expecting mothers. Next, we will discuss the possible action of BPA on the epigenetic mechanism during brain development. This is especially important to portray an overview on the role of epigenetic modification caused by prenatal BPA exposure and next, give future directions for improving human health risk assessment caused by BPA exposure., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bisphenol A (BPA), chemically known as 2,2-bis(4-hydroxyphenyl) propane, is one of the most common endocrine-disrupting chemicals in our environment. Long-term or high-dose exposure to BPA may lead to testicular damage and adversely affect male reproductive function. In vivo studies on rodents have demonstrated that BPA triggers apoptosis in testicular cells through both intrinsic and extrinsic pathways. Further in vitro studies on spermatogonia, Sertoli cells, and Leydig cells have all confirmed the pro-apoptotic effects of BPA. Given these findings, apoptosis is considered a primary mode of cell death induced by BPA in testicular tissue. In addition, BPA promotes autophagy by altering the activity of the Akt/mTOR pathway and upregulating the expression of autophagy-related genes and proteins. Recent studies have also identified ferroptosis as a significant contributing factor to BPA-induced testicular damage, further complicating the landscape of BPA's effects. This review summarizes natural substances that mitigate BPA-induced testicular damage by inhibiting these cell death pathways. These findings not only highlight potential therapeutic strategies but also underscore the need for further research into the underlying mechanisms of BPA-induced toxicity, particularly as it pertains to human health risk assessment and the development of more effective BPA management strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pyrethroids are widely used insecticides with huge applications for household as well as agricultural purposes and contribute to improved product quality and higher yields. In recent decades, the demand for pyrethroids has increased significantly due to advantages such as broad-spectrum efficacy, high insecticidal potential, and lower pest resistance. However, several studies have suggested that human exposure to pyrethroids leads to reproductive problems. Sex hormone-binding globulin (SHBG) is an important hormone transport protein regulating the availability of steroids at their target site. The aim of our study was to investigate the structural interactions of commonly used pyrethroids, cypermethrin and deltamethrin, with ligand binding pocket of SHBG. Cypermethrin and deltamethrin were docked into the steroid binding pocket of SHBG using Schrodinger's induced fit docking (IFD) followed by molecular dynamics (MD) simulation studies. The resultant SHBG-pyrethroid complexes from IFD experiments were subjected to structural analysis including the molecular interactions followed by binding energy estimation. The analysis revealed that both the ligands were tightly bound in the SHBG pocket with high percentage of commonality among the SHBG residues between the indicated pyrethroid ligands and the SHBG native ligand, dihydrotestosterone (DHT). The estimated binding energy values for cypermethrin were less but close to the values calculated for the SHBG native ligand, DHT. However, the estimated binding energy values for deltamethrin were higher compared to the values calculated for SHBG native ligand, DHT. Furthermore, the MD simulation results also revealed the higher stability of SHBG-deltamethrin than SHBG-cypermethrin complex. To sum up, the results suggested that deltamethrin has a greater capability than cypermethrin to prevent sex steroid hormone from binding to SHBG, even though both pyrethroids have this ability. Consequently, this might hamper the circulatory transport of sex steroid hormones and their availability at the target site, subsequently interfering with reproductive function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;43:2329-2337. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

The investigation of pollutant inputs via stormwater runoff and subsequent effects in receiving waters is becoming increasingly urgent in view of climate change with accompanying extreme weather situations such as heavy rainfall events. In this study, two sampling areas, one urban and one rural but dominated by a highway, were investigated using effect-directed analysis to identify endocrine and neurotoxic effects and potentially responsible substances in stormwater structures and receiving waters. For this purpose, a transgenic yeast cell assay for the simultaneous detection of estrogenic, androgenic, and progestogenic effects (YMEES) was performed directly on high-performance thin-layer chromatography (HPTLC) plates. Concomitantly, estrogens were analyzed by GC-MS/MS and other micropollutants typical for wastewater and stormwater by LC-MS/MS. Discharges from the combined sewer overflow (CSO) contribute a large portion of the endocrine load to the studied water body, even surpassing the load from a nearby wastewater treatment plant (WWTP). An effect pattern similar to the CSO sample was shown in the receiving water after the CSO with lower intensities, consisting of an estrogenic, androgenic, and progestogenic effect. In contrast, after the WWTP, only one estrogenic effect with a lower intensity was detected. Concentrations of E1, 17α-E2, 17β-E2, EE2, and E3 in the CSO sample were 2000, 410, 1100, 560, and 2700 pg/L, respectively. HPTLC-YMEES and GC-MS/MS complement each other very well and help to elucidate endocrine stresses. An Acetylcholinesterase (AChE) inhibitory effect could not be assigned to a causative compound by suspect and non-target analysis using LC-HRMS. However, the workflow showed how information from HPTLC separation, effect-based methods, and other meta-information on the sampling area and substance properties can contribute to an identification of effect-responsible substances. Overall, the study demonstrated that effect-based methods in combination with HPTLC and instrumental analysis can be implemented to investigate pollution by stormwater run-off particularly regarding heavy rain events due to climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Bisphenol A (BPA) is a chemical substance used in the plastic industry and considered as an endocrine disruptor. Ginger is a herbal material used in the food industry and has antioxidant activity. The present study was performed to evaluate the histological changes in the thyroid gland of adult male albino rats after intake of BPA and if there is any protective role for ginger extract (GE). Eighty adult male rats were divided equally into four groups. Group I as a control group, group II included rats that received 250 mg/kg/day GE orally for eight weeks, group III included rats that received 200 mg/kg/day BPA orally for the same period and group IV included rats that received BPA in the same dose for the same duration concomitantly with GE. At the end of the experiment, blood samples were taken for hormonal essay and tissue samples were processed. Light and electron microscopic studies were done. Morphometric and statistical studies were carried out. Group III showed degenerative changes in the thyroid gland, decreased serum levels of T3 and T4 and a strong positive inducible nitric oxide synthase (iNOS) immune response. Group IV showed restoration of thyroid gland architecture and function. In conclusion, GE protected the thyroid structure from the damaging effect of BPA oxidative stress through its anti-oxidant effect, thus preserving thyroid activity.

Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre-puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre-pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound., (© 2024 Wiley Periodicals LLC.)

Arsenic, a well-known hazardous toxicant, has been found in recent years to act as an environmental endocrine disruptor that accumulates in various endocrine organs, impeding the normal physiological functions of these organs and altering hormone secretion levels. Moreover, some research has demonstrated a correlation between arsenic exposure and thyroid functions, suggesting that arsenic has a toxicological effect on the thyroid gland. However, the specific type of thyroid gland damage caused by arsenic exposure and its potential molecular mechanism remain poorly understood. In this study, the toxic effects of sodium arsenite (NaAsO 2 ) exposure at different doses (0, 2.5, 5.0 and 10.0 mg/kg bw) and over different durations (12, 24 and 36 weeks) on thyroid tissue and thyroid hormone levels in Sprague‒Dawley (SD) rats were investigated, and the specific mechanisms underlying the effects were also explored. Our results showed that NaAsO 2 exposure can cause accumulation of this element in the thyroid tissue of rats. More importantly, chronic exposure to NaAsO 2 significantly upregulated the expression of NLRP3 inflammasome-related proteins in thyroid tissue, leading to pyroptosis of thyroid cells and subsequent development of thyroid dysfunction, inflammatory injury, epithelial-mesenchymal transition (EMT), and even fibrotic changes in the thyroid glands of SD rats. These findings increase our understanding of the toxic effects of arsenic exposure on the thyroid gland and its functions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this presented study, the aim was to investigate the toxic effects of bisphenol S (BPS), one of the bisphenol A analogues, on the thyroid glands of male Wistar albino rats. Toward this aim, the rats ( n = 28) were given a vehicle (control) or BPS at 3 different doses, comprising 20, 100, and 500 mg/kg of body weight (bw) via oral gavage for 28 days. According to the results, BPS led to numerous histopathological changes in the thyroid tissue. The average proliferation index values among the thyroid follicular cells (TFCs) displayed increases in all of the BPS groups, and significant differences were observed in the BPS-20 and BPS-100 groups. The average apoptotic index values in the TFCs were increased significantly in the BPS-500 group. The serum thyroid-stimulating hormone and serum free thyroxine levels did not show significant changes after exposure to BPS; however, the serum free triiodothyronine levels displayed significant decreases in all 3 of the BPS groups. BPS was determined to cause significant increases in the antioxidant enzyme activities of catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, as well as a significantly decreased content of reduced glutathione. The malondialdehyde level in the thyroid tissue was elevated significantly in the BPS-500 group. The data obtained herein revealed that BPS has thyroid-disrupting potential based on structural changes, follicle cell responses, and biochemical alterations including a decreased serum free triiodothyronine level and increased oxidative stress., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Gestating mice were exposed to three chemicals, tetrabromo-bisphenol A (TBBPA; 2 mg/kg/day), amitrole (25 and 50 mg/kg/day) and pyraclostrobin (0.4 and 2 mg/kg/day) to assess their capacity to act as thyroid hormone disruptors and compromise neurodevelopment. Propyl-thio-uracyl, a known pharmacological inhibitor of thyroid gland secretion, was used at both high and low dose as a reference thyroid hormone system disruptor (1 ppm, 1500 ppm). A combination of plasma metabolomics and striatum transcriptomics revealed the induced change in pups at the postnatal stages. Although the underlying mechanism is unlikely to involve thyroid hormone disruption, these chemicals had a detectable effect on pups' neurodevelopment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bisphenol P (BPP) has been detected in human biological samples; however studies on its nephrotoxicity are scarce. Given the susceptibility of kidneys to endocrine-disrupting chemicals, there is an urgent need to investigate the renal toxicity of BPP. This study aimed to evaluate the effects of different concentrations of BPPs on the kidneys of C57BL/6 mice and elucidate the underlying mechanisms of renal damage using a combination of mouse renal transcriptomic data and human renal proximal tubular epithelial cells (HK-2). Mice were exposed to BPP (0, 0.3, 30, 3000 μg/kg bw/d) via gavage for 5 weeks. Renal injury was assessed based on changes in body and kidney weights, serum renal function indices, and histopathological examination. Transcriptomic analysis identified differentially expressed genes and pathways, whereas cellular assays were used to measure cell viability, reactive oxygen species (ROS), apoptosis, and the expression of key genes and proteins. The results show that BPP exposure induces renal injury, as evidenced by increased body weight, abnormal renal function indices, and renal tissue damage. Transcriptomic analysis revealed alterations in genes and pathways related to oxidative stress, p53 signaling, autophagy, and apoptosis. Cellular experiments confirmed that BPP induces oxidative stress and apoptosis. Furthermore, BPP exposure significantly inhibits autophagy, potentially exacerbating apoptosis and contributing to kidney injury. Treatment with a ROS inhibitor (N-Acetylcysteine, NAC) mitigated BPP-induced autophagy inhibition and apoptosis, implicating oxidative stress as a key factor. BPP exposure may lead to renal injury through excessive ROS accumulation, oxidative stress, inflammatory responses, autophagy inhibition, and increased apoptosis. The effects of NAC highlight the role of oxidative stress in BPP-induced nephrotoxicity. These findings enhance our understanding of BPP-induced nephrotoxicity and underscore the need to control BPP exposure to prevent renal disease. This study emphasized the importance of evaluating the safety of new Bisphenol A analogs, including BPP, in environmental toxicology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl 2 ) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl 2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue., (© 2024 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Phthalates are a class of known endocrine-disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 h in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1 to 100 μg/ml). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The frequency of detection and concentrations of bifenthrin, a pyrethroid insecticide, in the waterways inhabited by the endangered species, steelhead trout (Oncorhynchus mykiss), has become a significant concern for regulatory agencies. Endocrine disruption has been observed with estrogenic and anti-estrogenic responses in fish species at different life stages. Since several studies have indicated alterations in dopaminergic signaling associated with endocrine responses, juvenile steelhead were exposed to environmentally relevant concentrations of 60 or 120 ng/L bifenthrin for two weeks. Fish brains were assessed for dopamine levels and the expression of genes involved in dopaminergic and estrogenic processes, such as catechol-o-methyltransferase (comt) and monoamine oxidase (mao). Vitellogenin (vtg) and estrogenic receptors (ERα1, ERβ1, and ERβ2) were also evaluated in livers of the animals. Dopamine concentrations were significantly higher in fish brains following bifenthrin exposure. Consistent with a reduction in dopamine clearance, there was a significant decrease in the mRNA expression of comt with increased bifenthrin concentration. Hepatic expression of ERα1 and ERβ2 mRNA was significantly decreased with increased bifenthrin concentration. These data support the possible mechanism of bifenthrin altering the dopaminergic pathway at low ng/L concentrations, in juvenile steelhead, which could interfere with endocrine feedback loops. These findings support the need for and importance of identifying species and life stage differences in pesticide modes of action to reduce uncertainties in risk assessments., Competing Interests: Declaration of competing interest The authors declare no competing financial interest or personal relationships that could have appeared to influence the work reported in this paper. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government., (Published by Elsevier Inc.)

Polychlorinated biphenyls (PCBs) are industrial pollutants that act as endocrine disruptors and alter thyroid function. However, it is still unclear whether PCBs can affect hypothalamic thyrotropin releasing hormone (Trh) mRNA expression through TH signaling disruption. As salt-loading dehydration induces tertiary hypothyroidism in the hypothalamic parvocellular paraventricular nuclei (paPVN), and perinatal exposure to Aroclor 1254 (A1254) disrupts the hydric balance in rats, we hypothesized that TRH synthesis could be altered during dehydration in TRH neurons that control the hypothalamic-pituitary-thyroid (HPT) axis activity in rats perinatally exposed to A1254. We examined Trh mRNA expression in the paPVN and the response to salt-loading dehydration (hyperosmotic (hyper) stress) in the progeny of Wistar pregnant rats receiving 0 mg/kg BW (control) or 30 mg/kg BW A1254 daily from gestational days 10-19. Three-month-old offspring were subjected to normosmotic or hyper conditions and Trh mRNA, glucocorticoid receptor (GR) mRNA expression were measured in the PVN by RT-PCR. TRH mRNA and TRH+ neurons were measured in the paPVN by fluorescent in situ hybridization (FISH). As expected, Trh mRNA levels were decreased in the paPVN of male and female rats in the hyper group. Basal Trh mRNA expression and serum TSH were decreased in male rats in the A1254 group. Notably, Trh mRNA levels were further decreased in the paPVN of male and female A1254 + hyper rats, in which the GR mRNA expression was significantly decreased. These results support the hypothesis that perinatal exposure to A1254 results in inadequate adaptive response of the HPT axis in adulthood and contributes to dysregulation of the HPT axis response to salt-loading dehydration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Every year the global incidence of obesity increases considerably and among the factors that favor it is bisphenol A (BPA), an endocrine disruptor widely used in plastics and omnipresent in many everyday objects., Methods: A total of 19 studies published between 2018 and 2023 that addressed the relationship between BPA exposure and obesity were included in this review in order to better understand its behavior and mechanisms of action., Results: The studies reviewed conclude that BPA is an obesogen that alters the function of hormonal receptors, promotes metabolic syndrome, affects certain genes, etc., leading to a greater risk of developing obesity. With important emphasis on the ability to cause epigenetic changes, thus transmitting the effects to offspring when exposure has occurred during critical stages of development such as during gestation or the perinatal period., Conclusions: There is sufficient evidence to show that BPA is a risk factor in the development of obesity. Even so, further research is necessary to exhaustively understand the causal relationship between the two in order to develop prevention measures and avoid possible future adverse effects.