Estrogen-related receptor, a molecular target against lepidoptera pests.

Until recently, chemical pesticides were one of the most effective means of controlling agricultural pests; therefore, the search for insecticide targets for agricultural pests has been an ongoing problem. Estrogen-related receptors (ERRs) are transcription factors that regulate cellular metabolism and energy homeostasis in animals. Silkworms are highly sensitive to chemical pesticides, making them ideal models for pesticide screening and evaluation. In this study, we detected ERR expression in key organs involved in pesticide metabolism in silkworms (Bombyx mori), including the fat body and midgut. Using ChIP-seq technology, many estrogen- related response elements were identified in the 2000-bp promoter region upstream of metabolism-related genes, almost all of which were potential ERR target genes. The ERR inhibitor, XCT-790, and the endocrine disruptor, bisphenol A, significantly inhibited expression of the ERR target genes, BmTreh-1, BmTret-1, BmPK, BmPFK, and BmHK, in the fat bodies of silkworms, resulting in pupation difficulties in silkworm larvae that ultimately lead to death. In addition, based on the clarification that the ERR can bind to XCT-790, as observed through biofilm interferometry, its three-dimensional spatial structure was predicted, and using molecular docking techniques, small-molecule compounds with a stronger affinity for the ERR were identified. In summary, utilizing the powerful metabolic regulatory function of ERR in Lepidoptera pests, the developed small molecule inhibitors of ERR can be used for future control of Lepidoptera pests.

Nonylphenol releases arachidonic acid in rat Sertoli cells via activation of PKA and PLA2.

In brief: The endocrine disruptor, nonylphenol (NP) increases 20:4n-6 release in Sertoli cells via PKA/cPLA2 activation. Our data show that lipid metabolism could be a target of NP-induced abnormal reproductive outcomes. Abstract: Nonylphenol (NP), an endocrine-disrupting chemical, is an environmental contaminant, and many notorious effects on male fertility have been reported in animal models and wild-type species. Here, we evaluated the effects of NP in follicle-stimulating hormone (FSH) signal transduction pathways and lipid metabolism using an in vitro model of rat Sertoli cell (SC) primary culture. Results show that an acute (1 h) SC exposure to NP (10 µM) increased the intra- and extra-cellular concentrations of free fatty acids (FFAs), mainly arachidonic acid (20:4n-6). Phosphatidylinositol seemed to be the major phospholipid source of this 20:4n-6 release by activation of the protein kinase A (PKA)/cytoplasmic phospholipase A2 (cPLA2) pathway. NP also increased diacylglycerols (DAG) levels and the expression (mRNA) of cyclooxygenase 2 (Cox2) and prostaglandin E2 (PGE2) levels. It is noteworthy that accumulation of lipid droplets took place after 24 h NP exposition, which was prevented by both a PKA inhibitor and a PLA2 inhibitor. Like FSH, NP triggers the release of 20:4n-6, which is a substrate for PGE2 synthesis via PKA/PLA2 activation. In addition, NP induces the formation of DAG, which could be required as a cofactor of the PKC-mediated activation of the COX2 inflammatory pathway. Our findings suggest that NP alters lipid homeostasis in SCs by inducing the activation of pro-inflammatory pathways that may trigger adverse effects in testis physiology over time. Concomitantly, the SC enhances the acylation of surplus FFAs (including 20:4n-6) in neutral lipids as a protective mechanism to shield itself from lipotoxicity and pro-inflammatory signals.

Concept of a six-fold multiplex planar bioassay to distinguish endocrine agonist, antagonist, cytotoxic and false-positive responses.

To analyze a complex sample for endocrine activity, different tests must be performed to clarify androgen/estrogen agonism, antagonism, cytotoxicity, anti-cytotoxicity, and corresponding false-positive reactions. This means a large amount of work. Therefore, a six-fold planar multiplex bioassay concept was developed to evaluate up to the mentioned six endpoints or mechanisms simultaneously in the same sample analysis. Separation of active constituents from interfering matrix via high-performance thin-layer chromatography and effect differentiation via four vertical stripes (of agonists and end-products of the respective enzyme-substrate reaction) applied along each separated sample track were key to success. First, duplex endocrine bioassay versions were established. For the androgen/anti-androgen bioassay applied via piezoelectric spraying, the mean limit of biological detection of bisphenol A was 14 ng/band and its mean half maximal inhibitory concentration IC50 was 116 ng/band. Applied to trace analysis of six migrate samples from food packaging materials, 19 compound zones with agonistic or antagonistic estrogen/androgen activities were detected, with up to seven active compound zones within one migrate. For the first time, the S9 metabolism of endocrine effective compounds was studied on the same surface and revealed partial deactivation. Coupled to high-resolution mass spectrometry, molecular formulas were tentatively assigned to compounds, known to be present in packaging materials or endocrine active or previously unknown. Finally, the detection of cytotoxicity/anti-cytotoxicity and false-positives was integrated into the duplex androgen/anti-androgen bioassay. The resulting six-fold multiplex planar bioassay was evaluated with positive control standards and successfully applied to one migrate sample. The streamlined stripe concept for multiplex planar bioassays made it possible to assign different mechanisms to individual active compounds in a complex sample. The concept is generic and can be transferred to other assays.

Single and mixture effects of bisphenol A and benzophenone-3 on in vitro T helper cell differentiation.

Immune homeostasis is key to guarantee that the immune system can elicit effector functions against pathogens and at the same time raise tolerance towards other antigens. A disturbance of this delicate balance may underlie or at least trigger pathologies. Endocrine disrupting chemicals (EDCs) are increasingly recognized as risk factors for immune dysregulation. However, the immunotoxic potential of specific EDCs and their mixtures is still poorly understood. Thus, we aimed to investigate the effect of bisphenol A (BPA) and benzophenone-3 (BP-3), alone and in combination, on in vitro differentiation of T helper (TH)17 cells and regulatory T (Treg) cells. Naïve T cells were isolated from mouse lymphoid tissues and differentiated into the respective TH population in the presence of 0.001-10 µM BP-3 and/or 0.01-100 µM BPA. Cell viability, proliferation and the expression of TH lineage specific transcription factors and cytokines was measured by flow cytometry and CBA/ELISA. Moreover, the transcription of hormone receptors as direct targets of EDCs was quantified by RT-PCR. We found that the highest BPA concentration adversely affected TH cell viability and proliferation. Moreover, the general differentiation potential of both TH populations was not altered in the presence of both EDCs. However, EDC exposure modulated the emergence of TH17 and Treg cell intermediate states. While BPA and BP-3 promoted the development of TH1-like TH17 cells under TH17-differentiating conditions, TH2-like Treg cells occurred under Treg polarization. Interestingly, differential effects could be observed in mixtures of the two tested compounds compared with the individual compounds. Notably, estrogen receptor ß expression was decreased under TH17-differentiating conditions in the presence of BPA and BP-3 as mixture. In conclusion, our study provides solid evidence for both, the immune disruptive potential and the existence of cumulative effects of real nature EDC mixtures on T cell in vitro differentiation.

Plastic Food Packaging from Five Countries Contains Endocrine- and Metabolism-Disrupting Chemicals.

Plastics are complex chemical mixtures of polymers and various intentionally and nonintentionally added substances. Despite the well-established links between certain plastic chemicals (bisphenols and phthalates) and adverse health effects, the composition and toxicity of real-world mixtures of plastic chemicals are not well understood. To assess both, we analyzed the chemicals from 36 plastic food contact articles from five countries using nontarget high-resolution mass spectrometry and reporter-gene assays for four nuclear receptors that represent key components of the endocrine and metabolic system. We found that chemicals activating the pregnane X receptor (PXR), peroxisome proliferator receptor γ (PPARγ), estrogen receptor α (ERα), and inhibiting the androgen receptor (AR) are prevalent in plastic packaging. We detected up to 9936 chemical features in a single product and found that each product had a rather unique chemical fingerprint. To tackle this chemical complexity, we used stepwise partial least-squares regressions and prioritized and tentatively identified the chemical features associated with receptor activity. Our findings demonstrate that most plastic food packaging contains endocrine- and metabolism-disrupting chemicals. Since samples with fewer chemical features induce less toxicity, chemical simplification is key to producing safer plastic packaging.

Cuscuta chinensis flavonoids alleviate ovarian damage in offspring female mice induced by BPA exposure during pregnancy by regulating the central carbon metabolism pathway.

Pregnancy is a sensitive window period for bisphenol A (BPA) exposure. BPA can pass through the placenta and cause reproductive damage in offspring female mice. Even BPA that is not metabolized during lactation can be passed through milk. Cuscuta chinensis flavonoids (CCFs) can alleviate reproductive damage caused by BPA, but the mechanism of action is unclear. To investigate the potential mitigating impact of CCFs on ovarian damage resulting from BPA exposure during pregnancy, we administered BPA and CCFs to pregnant mice during the gestational period spanning from 0.5 to 17.5 days. Aseptic collection of serum and ovaries from female mice was conducted on postnatal day 21 (PND21). Serum hormone levels and tissue receptor levels were quantified utilizing ELISA and PCR, while ovaries underwent sequencing and analysis through transcriptomics and metabolomics techniques. Additionally, the assessment of ovarian oxidative stress levels was carried out as part of the comprehensive analysis. The results showed that CCFs administration mitigated the adverse effects induced by BPA exposure on ovarian index, hormone levels, receptor expression, and mRNA expression levels in female offspring mice. The joint analysis of transcriptome and metabolome revealed 48 enriched pathways in positive ion mode and 44 enriched pathways in negative ion mode. Among them, the central carbon metabolism pathway is significantly regulated by BPA and CCFs. The screened sequencing results were verified through qPCR and biochemical kits. In this study, CCFs may participate in the central carbon metabolism pathway by reducing the expression of Kit proto-oncogene (Kit), hexokinase 1 gene (Hk1) and pyruvate kinase M (Pkm) mRNA and increasing the expression of h-ras proto-oncogene (Hras), sirtuin 3 (Sirt3), sirtuin 6 (Sirt6) and TP53 induced glycolysis regulatory phosphatase gene (Tigar) mRNA, thereby resisting the effects of BPA on the body. At the same time, the metabolic levels of D-Fructose 1,6-bisphosphate and L-Asparagine tend to be stable. Moreover, CCFs demonstrated a capacity to diminish the BPA-induced escalation in reactive oxygen species (ROS) and malondialdehyde (MDA). Simultaneously, it exhibited the ability to elevate levels of glutathione (GSH) and catalase (CAT), thereby effectively preventing peroxidation. In summary, CCFs alleviate BPA-induced ovarian damage in offspring female mice by regulating the central carbon metabolism pathway. This study will improve the information on BPA reproductive damage antagonist drugs and provide a theoretical basis for protecting animal reproductive health.

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

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

The Caenorhabditis elegans neuroendocrine system and their modulators: An overview.

In this review we seek to systematically bring what has been published in the literature about the nervous system, endocrine system, neuroendocrine relationships, neuroendocrine modulations and endocrine disruptors in the alternative model Caenorhabditis elegans. The serotonergic, dopaminergic, GABAergic and glutamatergic neurotransmitters are related to the modulation of the neuroendocrine axis, leading to the activation or inhibition of several processes that occur in the worm through distinct and interconnected pathways. Furthermore, this review addresses the gut-neuronal axis as it has been revealed in recent years that gut microbiota impacts on neuronal functions. This review also approaches xenobiotics that can positively or negatively impact the neuroendocrine system in C. elegans as in mammals, which allows the application of this nematode to screen new drugs and to identify toxicants that are endocrine disruptors.

[Synthetic phenolic compounds perturb lipid metabolism and induce obesogenic effects].

Given continuous development in society and the economy, obesity has become a global epidemic, arousing great concern. In addition to genetic and dietary factors, exposure to environmental chemicals is associated with the occurrence and development of obesity. Current research has indicated that some chemicals with endocrine-disrupting effects can affect lipid metabolism in vivo, causing elevated lipid storage. These chemicals are called "environmental obesogens". Synthetic phenolic compounds (SPCs) are widely used in industrial and daily products, such as plastic products, disinfectants, pesticides, food additives, and so on. The exposure routes of SPCs to the human body may include food and water consumption, direct skin contact, etc. Their unintended exposure could cause harmful effects on human health. As a type of endocrine disruptor, SPCs interfere with adipogenesis and lipid metabolism, exhibiting the characteristics of environmental obesogens. Because SPCs have similar phenolic structures, gathering information on their influences on lipid metabolism would be helpful to understand their structure-related effects. In this review, three commonly used research methods for screening environmental obesogens, including in vitro testing for molecular interactions, cell adipogenic differentiation models, and in vivo studies on lipid metabolism, are summarized, and the advantages and disadvantages of these methods are compared and discussed. Based on both in vitro and in vivo data, three types of SPCs, including bisphenol A (BPA) and its analogues, alkylphenols (APs), and synthetic phenolic antioxidants (SPAs), are systematically discussed in terms of their ability to disrupt adipogenesis and lipid metabolism by focusing on adipose and hepatic tissues, among others. Common findings on the effects of these SPCs on adipocyte differentiation, lipid storage, hepatic lipid accumulation, and liver steatosis are described. The underlying toxicological mechanisms are also discussed from the aspects of nuclear receptor transactivation, inflammation and oxidative stress regulation, intestinal microenvironment alteration, epigenetic modification, and some other signaling pathways. Future research to increase public knowledge on the obesogenic effects of emerging chemicals of concern is encouraged.

Antidepressants - The new endocrine disruptors? The case of crustaceans.

Antidepressants are high-volume pharmaceuticals that accumulate to concentrations in the µg·L-1 range in surface waters. The release of peptide hormones via neurosecretory cells appears as a natural target for antidepressants. Here I review research that suggests that antidepressants indeed disrupt endocrine signalling in crustaceans, by acting on the synthesis and release of neurohormones, such as crustacean hyperglycaemic hormone, moult inhibiting hormone and pigment dispersing hormone in decapods, as well as methyl farnesoate in Daphnids. Hence, antidepressants can affect hormonal regulation of physiological functions: increase in energy metabolism and activity, lowered ecdysteroid levels, potentially disrupting moult and somatic growth, reducing colour change capacity and compromising camouflage, as well as induction of male sex determination. Several studies further suggest effects of antidepressants on crustacean reproduction, but the hormonal regulation of these effects remains elusive. All things considered, a body of evidence strongly suggests that antidepressants are endocrine disrupting compounds in crustaceans.

The endocrine disruptor cadmium modulates the androgen-estrogen receptors ratio and induces inflammatory cytokines in luminal (A) cell models of breast cancer.

PURPOSE: Breast cancer (BC) is the most common malignancy that affects women, and it is, to date, their leading cause of death. Luminal A molecular subtype accounts for 40% of BC and is characterized by hormone receptors positive/human epidermal growth factor 2 expression and current treatment consists of surgery plus aromatase inhibitor therapy. Interestingly, several studies demonstrated that the heavy metal cadmium (Cd), classified as a group 1 human carcinogen and widely spread in the environment, exerts estrogen-like activities in several tissues and suggested an intriguing relationship between increased Cd exposure and BC incidence. Thus, aim of this study was to evaluate effects of Cd on Luminal A BC estrogen receptor (ER) positive/progesterone receptor positive cell models in vitro to characterize the mechanism(s) involved in breast cell homeostasis disruption. METHODS: T47D and MCF7 were exposed to Cd (0.5-1 µM) for 6-24 h to evaluate potential alterations in: cells viability, steroid receptors and intracellular signaling by western blot. Moreover, we evaluated the expression of inflammatory cytokines interleukin by RT-PCR. RESULTS: Our results showed a significant induction of androgen receptor (AR) and an increased AR/ER ratio. Further, Cd exposure increased pro-inflammatory cytokines interleukin (IL)6, IL8 and tumor necrosis factor α levels. Finally, as previously demonstrated by our group, Cd alters pathways such as mitogen-activated protein kinase family and protein kinase B. CONCLUSION: In conclusion, our study demonstrates that Cd modifies the expression and pattern of ERs and AR in BC cell lines, suggesting an alteration of BC cells homeostasis, likely predisposing to a carcinogenetic microenvironment.

[Disruptors of thyroid hormones: Which consequences for human health and environment?] / Les perturbateurs des hormones thyroïdiennes : comment estimer leurs impacts sur la santé humaine et l'environnement ?

Endocrine disruptors (EDs) of chemical origin are the subject of numerous studies, some of which have led to measures aimed at limiting their use and their impact on the environment and human health. Dozens of hormones have been described and are common to all vertebrates (some chemically related messengers have also been identified in invertebrates), with variable roles that are not always known. The effects of endocrine disruptors therefore potentially concern all animal species via all endocrine axes. These effects are added to the other parameters of the exposome, leading to strong, multiple and complex adaptive pressures. The effects of EDs on reproductive and thyroid pathways have been among the most extensively studied over the last 30 years, in a large number of species. The study of the effects of EDs on thyroid pathways and brain development goes hand in hand with increasing knowledge of 1) the different roles of thyroid hormones at cellular or tissue level (particularly developing brain tissue) in many species, 2) other hormonal pathways and 3) epigenetic interactions. If we want to understand how EDs affect living organisms, we need to integrate results from complementary scientific fields within an integrated, multi-model approach (the so-called translational approach). In the present review article, we aim at reporting recent discoveries and discuss prospects for action in the fields of medicine and research. We also want to highlight the need for an integrated, multi-disciplinary approach to studying impacts and taking appropriate action.

Title: Les perturbateurs des hormones thyroïdiennes : comment estimer leurs impacts sur la santé humaine et l'environnement ? Abstract: Les perturbateurs endocriniens (PE) d'origine chimique font l'objet de nombreuses études, certaines ayant permis des mesures visant à limiter leur utilisation et leurs impacts sur l'environnement et la santé humaine. Des dizaines d'hormones ont été décrites et sont communes à l'ensemble des vertébrés (certains messagers chimiquement proches ont été également répertoriés chez les invertébrés) avec des rôles variables et pas toujours connus. Les effets des PE concernent donc potentiellement toutes les espèces animales via tous les axes endocriniens ; ils s'ajoutent aux autres paramètres de l'exposome qui induisent une pression d'adaptation forte, multiple, et difficile à appréhender. Les effets des PE sur les voies de la reproduction et les voies thyroïdiennes sont parmi les plus étudiés depuis ces trente dernières années et ce, sur un grand nombre d'espèces. L'étude des effets des PE sur les voies thyroïdiennes ainsi que sur le développement cérébral va de pair avec l'augmentation des connaissances sur 1) les différents rôles des hormones thyroïdiennes au niveau cellulaire ou tissulaire (notamment le tissu cérébral en développement) chez de nombreuses espèces, 2) les autres voies hormonales et 3) les interactions épigénétiques. De façon générale, si l'on veut appréhender comment agissent les PE sur les organismes vivants, il est nécessaire d'analyser dans une approche intégrée et multi-modèles (approche dite translationnelle) les résultats issus de domaines scientifiques complémentaires. Dans cette brève revue, nous dressons un état des lieux de découvertes récentes et discutons les perspectives d'action dans les champs de la médecine et de la recherche. Nous mettons en avant la nécessité d'une approche intégrée et multidisciplinaire pour étudier les impacts des PE et prendre des mesures appropriées.

The Effects of Combined Exposure to Bisphenols and Perfluoroalkyls on Human Perinatal Stem Cells and the Potential Implications for Health Outcomes.

The present study investigates the impact of two endocrine disruptors, namely Bisphenols (BPs) and Perfluoroalkyls (PFs), on human stem cells. These chemicals leach from plastic, and when ingested through contaminated food and water, they interfere with endogenous hormone signaling, causing various diseases. While the ability of BPs and PFs to cross the placental barrier and accumulate in fetal serum has been documented, the exact consequences for human development require further elucidation. The present research work explored the effects of combined exposure to BPs (BPA or BPS) and PFs (PFOS and PFOA) on human placenta (fetal membrane mesenchymal stromal cells, hFM-MSCs) and amniotic fluid (hAFSCs)-derived stem cells. The effects of the xenobiotics were assessed by analyzing cell proliferation, mitochondrial functionality, and the expression of genes involved in pluripotency and epigenetic regulation, which are crucial for early human development. Our findings demonstrate that antenatal exposure to BPs and/or PFs may alter the biological characteristics of perinatal stem cells and fetal epigenome, with potential implications for health outcomes at birth and in adulthood. Further research is necessary to comprehend the full extent of these effects and their long-term consequences.

Environmental endocrine disruptors and pregnane X receptor action: A review.

The pregnane X receptor (PXR) is a kind of orphan nuclear receptor activated by a series of ligands. Environmental endocrine disruptors (EEDs) are a wide class of molecules present in the environment that are suspected to have adverse effects on the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous hormones. Since EEDs may modulate human/rodent PXR, this review aims to summarize EEDs as PXR modulators, including agonists and antagonists. The modular structure of PXR is also described, interestingly, the pharmacology of PXR have been confirmed to vary among different species. Furthermore, PXR play a key role in the regulation of endocrine function. Endocrine disruption of EEDs via PXR and its related pathways are systematically summarized. In brief, this review may provide a way to understand the roles of EEDs in interaction with the nuclear receptors (such as PXR) and the related pathways.

Endocrine disrupting chemicals: A promoter of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder. With the improvement in human living standards, the prevalence of NAFLD has been increasing in recent years. Endocrine-disrupting chemicals (EDCs) are a class of exogenous chemicals that simulate the effects of hormones in the body. There has been growing evidence regarding the potential effects of EDCs on liver health, especially in NAFLD. This paper aims to summarize the major EDCs that contribute to the growing burden of NAFLD and to raise public awareness regarding the hazards posed by EDCs with the objective of reducing the incidence of NAFLD.

Differences in Age-Related Changes in the Thymus in Rats Developmentally Exposed to Endocrine Disrupter Dichlorodiphenyltrichloroethane.

We studied features of age-related changes in the thymus of mature male Wistar rats developmentally exposed to the endocrine disruptor dichlorodiphenyltrichloroethane (DDT). The study was carried out at the stage of early thymus involution. Differences in the thymus morphology associated with imbalance of morphogenetic processes in the cortex and medulla were observed after puberty in rats developmentally exposed to DDT. Increased proliferation of thymocytes, higher content of lymphoblasts, and concomitant decrease in T-cell migration in comparison with the control were found. Our findings indicate lower functional maturity of the thymus and prolonged disorders in the program of postnatal thymus development induced by the endocrine disruptor DDT.

The triazole fungicide metconazole inhibits the homodimerization of human androgen receptors to suppress androgen-induced transcriptional activation.

We assessed the mechanism of human androgen receptor-mediated endocrine-disrupting effect by a triazole fungicide, metconazole in this study. The internationally validated stably transfected transactivation (STTA) in vitro assay, which was established for determination of a human androgen receptor (AR) agonist/antagonist by using 22Rv1/MMTV_GR-KO cell line, alongside an in vitro reporter-gene assay to confirm AR homodimerization was used. The STTA in vitro assay results showed that metconazole is a true AR antagonist. Furthermore, the results from the in vitro reporter-gene assay and western blotting showed that metconazole blocks the nuclear transfer of cytoplasmic AR proteins by suppressing the homodimerization of AR. These results suggest that metconazole can be considered to have an AR-mediated endocrine-disrupting effect. Additionally, the evidence from this study might help identify the endocrine-disrupting mechanism of triazole fungicides containing a phenyl ring.

Cognitive and hippocampal effects of adult male mice exposure to environmentally relevant doses of phthalates.

We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 µg/kg/d) or to DEHP (5 µg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism.

Environmental estrogens shape disease susceptibility.

Along with industrialization, the environment is flooded with endocrine-disrupting chemicals, among which substances with estrogenic effects have attracted widespread attention in medical research. In terms of molecular mechanism, environmental estrogens can cause endocrine and metabolic disorders; interfere with multiple carcinogenic pathways; and lead to neurobehavioral disorders, reproductive toxicity, and multi- or trans-generational phenotypic abnormalities. However, many of the results from molecular and animal experiments were not supported by epidemiology, which may be related to the existence of a window of sensitivity to environmental estrogen exposure over the human life course, where the consequences of exposure vary greatly from other times. This paper will introduce the main sources of environmental estrogens, their toxicity and mechanisms of action, the status of research on several representative types, and current monitoring and treatment methods. We also discussed the extent of the risks to human health dialectically in the context of laboratory and epidemiological findings, with a view to better addressing these chemicals to which we are constantly exposed.

Fetal Exposure to Endocrine Disrupting-Bisphenol A (BPA) Alters Testicular Fatty Acid Metabolism in the Adult Offspring: Relevance to Sperm Maturation and Quality.

Daily exposure to bisphenols can affect reproductive functions due to their pseudo-estrogenic and/or anti-androgenic effects. Testicular lipids contain high levels of polyunsaturated fatty acids necessary for sperm maturity, motility, and spermatogenesis. Whether prenatal exposure to bisphenols alters testicular fatty acid metabolism in adult offspring is unknown. Pregnant Wistar rats were gavaged from gestational day 4 to 21 with BPA and BPS (0.0, 0.4, 4.0, 40.0 µg/kg bw/day). Despite increased body and testis weight, the total testicular cholesterol, triglyceride, and plasma fatty acids were unaffected in the offspring. Lipogenesis was upregulated by increased SCD-1, SCD-2, and expression of lipid storage (ADRP) and trafficking protein (FABP4). The arachidonic acid, 20:4 n-6 (ARA) and docosapentaenoic acid, 22:5 n-6 (DPA) levels were decreased in the BPA-exposed testis, while BPS exposure had no effects. The expression of PPARα, PPARγ proteins, and CATSPER2 mRNA were decreased, which are important for energy dissipation and the motility of the sperm in the testis. The endogenous conversion of linoleic acid,18:2 n-6 (LA), to ARA was impaired by a reduced ARA/LA ratio and decreased FADS1 expression in BPA-exposed testis. Collectively, fetal BPA exposure affected endogenous long-chain fatty acid metabolism and steroidogenesis in the adult testis, which might dysregulate sperm maturation and quality.