Environmental Endocrine-disrupting Chemicals Research Articles

Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis

BackgroundThe interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear.MethodsWe performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression.ResultsOur findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure.ConclusionThis study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

Molecular docking and molecular dynamics simulation decoding molecular mechanism of EDCs binding to hERRγ.

Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses.

Simultaneous determination of environmental endocrine disruptors bisphenol A and 4-nitrophenol bleached from food-contacting materials using the spin-ladder compound La2Cu2O5 modified glassy carbon electrode

Environmental endocrine-disrupting chemicals, Bisphenol A (BPA) and 4-Nitrophenol (4-NP), pose significant risks to reproductive health in both animals and humans. Here, we introduce the first utilization of the 4-leg spin ladder compound La2Cu2O5 as an electrode material for electrochemical sensor. Nanostructured La2Cu2O5 was synthesized via a straightforward Sol-Gel method and thoroughly characterized using X-ray photoelectron spectroscopy, high-resolution transmission electron microscopy, and powder X-ray diffraction. La2Cu2O5 nanoparticles modified glassy carbon electrode (GCE) exhibited a significant electrocatalytic activity towards the oxidation of BPA and 4-NP in phosphate buffer saline (pH 7.0). Square wave voltammetry studies revealed lowest detection limits of 3 nM for BPA and 2.6 nM for 4-NP over a wider concentration range of 0.01–500 μM. Notably, this study marks the first utilization of La2Cu2O5 for simultaneous electrochemical detection of BPA and 4-NP, demonstrating its potential in this field. Furthermore, the sensor exhibited good sensitivity, reproducibility, and selectivity towards BPA and 4-NP, even in the presence of similar potential organic and inorganic interferents. Additionally, the newly developed sensor enabled simultaneous quantification of BPA and 4-NP in real samples such as packaged milk, river water, and plastic bottles, achieving recovery rates above 95%. Importantly, our results underscore the leaching of BPA into water from thin and thick plastics at elevated temperatures (40 °C–80 °C), emphasizing the utility of the proposed sensor for rapid and simultaneous detection of BPA and 4-NP in environmental and food matrices.

Long-term impacts of endocrine-disrupting chemicals exposure on kidney function: A community-based cohort study

This study explores the extended renal effects of endocrine-disrupting chemicals (EDCs) exposure, a linkage already established with adverse health outcomes, notably chronic kidney disease. To delve deeper, the Chang Gung Community Research Center conducted a longitudinal study with 887 participants. Among them, 120 individuals were scrutinized based on EDC scores, analyzing 17 urinary EDCs and renal function. Findings revealed elevated mono-(2-ethylhexyl) phthalate (MEHP) and bisphenol A levels in higher EDC exposure cases. MEHP notably correlated with increased urinary albumin-to-creatinine ratio (UACR), predicting a > 15% decline in estimated glomerular filtration rate. Higher MEHP levels also hinted at declining renal function. UACR escalation linked significantly with specific EDCs: MEHP, methylparaben, nonylphenol, and 4-tert-octylphenol. This research underscores enduring renal hazards tied to environmental EDC exposure, particularly MEHP, emphasizing the urgent call for robust preventive public health strategies.

A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals

Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1.

Nontargeted Analysis Reveals a Broad Range of Bioactive Pollutants in Drinking Water by Estrogen Receptor Affinity-Mass Spectrometry.

Exposure to environmental endocrine-disrupting chemicals (EDCs) can cause extensive health issues. However, specific EDCs remain elusive. This work aimed at performing nontargeted identification of estrogen receptor α (ERα)-active compounds using an ERα protein affinity assay combined with high-resolution mass spectrometry in the source and drinking water sampled from major rivers in China. Fifty-one potential ERα-active compounds across 13 categories were identified. For the first time, diisodecyl phenyl phosphate was found to have antiestrogenic activity, and three chemicals (galaxolidone, bensulfuron methyl, and UV234) were plausible ERα ligands. Among the 51 identified compounds, 12 were detected in the aquatic environment for the first time, and the concentration of N-phenyl-2-naphthylamine, a widely used antioxidant in rubber products, was up to 1469 and 1190 ng/L in source and drinking water, respectively. This study demonstrated the widespread presence of known and unknown ERα estrogenic and antiestrogenic pollutants in the major rivers that serve as key sources of drinking water in China and the low removal efficiency of these chemicals in drinking water treatment plants.

Effects of combined exposure to polystyrene microplastics and 17α-Methyltestosterone on the reproductive system of zebrafish

Polystyrene microplastics (PS-MPs) are important carriers of pollutants in water. 17α-Methyltestosterone (MT) is a synthetic environmental endocrine disrupting chemical (EDC) with androgenic effects. To study the effects of PS-MPs and MT on zebrafish reproductive systems, zebrafish were exposed to 0 or 50 ng L−1 MT, 0.5 mg∙L−1 PS-MPs, or 50 ng∙L−1 MT + 0.5 mg∙L−1 PS-MPs for 21 d. The results showed that the different exposure reagents caused varying degrees of damage to the reproductive systems in zebrafish, with the extent of damage increasing as the exposure duration increased. Histological analysis of the gonads revealed that the ratio of mature oocytes and mature spermatozoa in the gonad decreased gradually with increased exposure time, with the ratio being Control > PS-MPs > MT > MT + PS-MPs in decreasing order. The results of quantitative real-time PCR (qRT‒PCR) showed that in female fish treated for 7 d, the expression of cyp11a mRNA was significantly reduced in all three treatment groups(MT, PS-MPs, and MT + PS-MPs), while in the group treated for 14 d with MT + PS-MPs, the expression of cyp19a1a and StAR mRNA was significantly increased. In male fish exposed for 21 d, the expression of cyp11a, cyp17a1, cyp19a1a, StAR, 3β-HSD, and 17β-HSD3 mRNA was significantly decreased in MT + PS-MPs. ELISA results showed that after 14 d of exposure, the levels of E2, LH, and FSH in the ovaries of female fish were significantly reduced in all three treatment groups. Similarly, the levels of T, E2, LH, and FSH in the testis of male fish were significantly reduced after 14 d of exposure to PS-MPs and MT + PS-MPs. Offspring of zebrafish exposed to MT and MT + PS-MPs exhibited delayed incubation time and slow development. The cross-generational toxicity of PS-MPs themselves may be negligible, but it can exacerbate the toxicity of MT, making the cross-generational effects more pronounced in the offspring, causing offspring mortality and malformations. Offspring of zebrafish exposed to MT and MT + PS-MPs exhibited delayed incubation time and slow development. In addition, MT caused malformations such as pericardial edema, yolk cysts, and spinal deformities in zebrafish during the incubation period.

Research progress on the interference effects of plasticizers on maternal behavior and its potential mechanisms.

Environmental endocrine disrupting chemicals (EDCs), known as environmental hormones, are exogenous chemicals that can disrupt hormone levels and cause dysfunction of the secretory system in humans and animals. Plasticizers, which are widely used EDCs, are commonly used to enhance the flexibility of plastic products. As plastics age and wear, however, they can leach into the environment and enter the bodies of animals through various pathways such as the digestive tract and skin. They can lead to estrogen-like effects and have substantial reproductive toxicity. Residual plasticizer concentrations in the environment are typically low. Unlike high doses that induce acute damage to the reproductive system, low doses of plasticizers do not cause macroscopic harm and thus its reproductive toxicity is often overlooked for extended periods. An increasing number of studies conducted on humans and mice in recent years have demonstrated that low doses of plasticizers can induce reproductive toxicity by interfering with maternal behavior. Prenatal exposure to plasticizers can result in abnormal postnatal maternal behavior. Female offspring also exhibit significantly low maternal care, lactation, and other behaviors in adulthood, which may persist for multiple generations, significantly disrupting the animal breeding process and impacting the health and well-being of newborn pups. The underlying mechanisms have not been systematically summarized. The risk of continuous exposure to low-dose plasticizers in humans and animals has increased due to the extensive utilization of plastic and rubber products in modern production and lifestyle patterns. It is thus crucial to conduct a systematic review on the effects of low-dose plasticizers on maternal behavior. We reviewed the research progress on the disruptive effects of plasticizers on animals' maternal behavior and concluded that these effects are primarily caused by inducing oxidative stress damage and DNA methylation reprogramming in the hypothalamic-pituitary-ovarian axis, as well as disrupting the balance of the thyroid system and causing intestinal microbial disorders. It would offer a novel perspective for future studies about the influence of plasticizers and other environmental hormones on maternal behavior in domesticated animals.

PCB126 impairs human sperm functions by affecting post-translational modifications and mitochondrial functions

Over the past few decades, there has been a consistent decline in semen quality across the globe, with environmental pollution being identified as the primary cause. Among the various contaminants present in the environment, persistent organic pollutants (POPs) have garnered significant attention due to their high toxicity, slow degradation, bio-accumulation, and long-range migration. PCBs, which include 210 congeners, are a crucial type of POPs that are known to have harmful effects on the environment and human health. Among the various PCB congeners, 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) is a typical environmental endocrine-disrupting chemical that is widely distributed and has been associated with several health hazards. However, the impact and mechanism of PCB126 on human sperm function has not been fully elucidated. We aimed to investigate the effects of different concentrations of PCB126 (0.01, 0.1, 1, 10 μg/mL) on sperm motility, viability, hyperactivation, and acrosome reaction after incubation for different periods (1 and 2 h), delving deeper into the molecular mechanism of human sperm dysfunction caused by PCB126. First, we investigated the link between PCB126 treatment and the occurrence of protein modifications that are critical to sperm function regulation, such as tyrosine phosphorylation and lysine glutarylation. Second, we examined the potential impact of PCB126 on different parameters related to mitochondrial function, including reactive oxygen species, malondialdehyde levels, mitochondrial membrane potential, mitochondria respiration and adenosine triphosphate generation. Our findings indicate that exposure to environmental pollutants such as PCB126 in vitro may have a negative impact on human sperm functions by interfering with post-translational modifications and mitochondrial functions.

In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse.

Thyroid hormones (TH) play a critical role in cell metabolism and tissue function. TH economy is susceptible to endocrine disrupting chemicals (EDCs) that can disturb hormone production or action. Many environmental pollutants are EDCs, representing an emerging threat to both human health and agricultural production. This has led to an increased demand for proper test systems to examine the effects of potential EDCs. However, current methodologies face challenges. Most test systems use endogenous markers regulated by multiple, often complex regulatory processes, making it difficult to distinguish direct and indirect effects. Moreover, in vitro test systems lack the physiological complexity of EDC metabolism and pharmacokinetics in mammals. Additionally, exposure to environmental EDCs usually involves a mixture of multiple compounds, including in vivo generated metabolites, so the possibility of interactions cannot be ignored. This complexity makes EDC characterization difficult. The Thyroid Hormone Action Indicator (THAI) mouse is a transgenic model that carries a TH-responsive luciferase reporter system, enabling the assessment of tissue-specific TH action. One can evaluate the tissue-specific effects of chemicals on local TH action by quantifying luciferase reporter expression in tissue samples. Furthermore, with in vivo imaging, the THAI mouse model allows for longitudinal studies on the effects of potential EDCs in live animals. This approach provides a powerful tool for testing long-term exposure, complex treatment structures, or withdrawal, as it enables the assessment of changes in local TH action over time in the same animal. This report describes the process of in vivo imaging measurements on THAI mice. The protocol discussed here focuses on developing and imaging hyper- and hypothyroid mice, which can serve as controls. Researchers can adapt or expand the treatments presented to meet their specific needs, offering a foundational approach for further investigation.

SAT425 Effects Of Endocrine-disrupting Polychlorinated Biphenyls On Adolescent Microglial Cytokine Expression And Responses To Secondary Inflammatory Challenge

Abstract Disclosure: S.L. Kissinger: None. A.J. Fitzgibbon: None. R.A. Mejia: None. M.R. Bell: None. Polychlorinated biphenyls (PCBs) are a group of ubiquitous environmental endocrine-disrupting chemicals (EDCs), and exposure is associated with endocrine, neuronal, and immune dysfunction in various tissue types. Innate immune cells of the nervous system called microglia are critical in responding to infection and injury, and disruption of these functions is associated with neurodegenerative disease and mental health disorders. In addition, microglia are known to regulate developmental processes during neonatal and adolescent periods, in hormone-sensitive and age- and sex-differentiated ways. Work in our lab has shown that early life PCBs can affect microglia function in ways that depend on the age and sex of the individual rat in vivo. Ongoing work uses in vitro approaches to demonstrate direct effects on microglia. In primary culture, preliminary data suggest that acute PCB exposure causes neonatal microglia to become hyperresponsive to a secondary challenge; however, effects in adolescent microglia are unknown. To test the hypothesis that PCB exposure directly alters microglia activity in an age- and sex-specific manner, we determined the effects of PCBs on cytokine gene expression in acutely isolated microglia, with or without a secondary lipopolysaccharide (LPS) challenge. Adolescent Sprague-Dawley rats underwent transcardial saline perfusion, brains were removed and homogenized into a single cell suspension with collagenase and mechanical disruption, and debris was removed. Microglia, identified as CD11b+ cells, were collected by magnetic bead isolation and plated in enriched media for 24 hours prior to experimentation. Cells were exposed to one of three concentrations of PCB 153 (0.1 µM, 1 µM, 10 µM), DMSO vehicle, or DMEM/F12 media control for 18 hours, followed by a 4-hour LPS challenge (0.5 µg/mL) or PBS vehicle control. RNA was isolated and converted to cDNA for qPCR analysis of Tnf and Il1b gene expression, analyzed by two-way (exposure x challenge) ANOVAs within both male and female cells. Results indicate that 1.0 µM PCB 153 exposure caused an increase in expression of both cytokines, more so in females than males. Preliminary results (n = 3) indicate that the 10 µM dose may also blunt the later LPS response. These results confirm that microglia are directly sensitive to PCBs, however they illustrate that cells may show differential responses depending on the stage of development. Continued work will explore acute cell toxicity and confirm release of cytokines. Adolescent microglia dysfunction from PCB exposure may be a mechanism of adolescent-onset disorders, or increased risk of neurodegenerative conditions triggered by additional challenges later in life. Presentation: Saturday, June 17, 2023

A pilot study of several environmental endocrine disrupting chemicals in children with autism spectrum disorder in south China.

Autism spectrum disorders (ASD) is a group of heterogeneous neurodevelopmental disorders. Evidence has implied that environmental pollutants are important factors related to ASD. In this study, several environmental endocrine-disrupting chemicals, including parabens, benzophenone-type ultraviolet filters, hydroxyl polycyclic aromatic hydrocarbons, triclosan and tetrabromobisphenol A were analyzed in blood plasma in ASD children (n = 34) and the control children (n = 28). The results showed that parabens were the most concentrated chemicals (2.18 ng/mL, median value), followed by hydroxyl polycyclic aromatic hydrocarbons (0.73 ng/mL), benzophenone-type ultraviolet filters (0.14 ng/mL), triclosan (0.13 ng/mL) and tetrabromobisphenol A (0.03 ng/mL). ASD children accumulated significantly lower 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 4-hydroxybenzophenone and triclosan but higher 2-hydroxyphenanthrene and tetrabromobisphenol A than the control children (0.02/0.09 ng/mL of 2-hydroxy-4-methoxybenzophenone, p < 0.05; 0.04/0.07 ng/mL of 2,4-dihydroxybenzophenone, p < 0.05; 0.03/0.04 ng/mL of 4-hydroxybenzophenone, p < 0.05; 0.13/1.22 ng/mL of triclosan, p < 0.01; 0.03 ng/mL/not detected of 2-hydroxyphenanthrene, p < 0.05; 0.03/0.004 ng/mL of tetrabromobisphenol A, p < 0.05). Gender differences in certain environmental endocrine-disrupting chemicals were evident, and the differences were more inclined toward boys. Positive associations between 2-hydroxy-4-methoxybenzophenone and triclosan, and tetrabromobisphenol A and 2-hydroxyphenanthrene were found in ASD boys. Binary logistic regression analysis showed that the adjusted odds ratio value of 2-hydroxyphenanthrene in ASD boys was 11.0 (1.45-84.0, p < 0.05). This is the first pilot study on multiple environmental endocrine-disrupting chemicals in children with ASD in China.

1680-P: Methyl Dihydrojasmonate (MDJ) Induces Hallmarks of Polycystic Ovary Syndrome (PCOS) and Related Mechanisms in Female Mice

More than half of polycystic ovary syndrome (PCOS) are overweight or obese. Environmental endocrine-disrupting chemicals (EDCs) are one of the important pathogenic factors in PCOS women. Methyl dihydrojasmonate (MDJ) is a food flavor additive, which can enter the body through several paths. However, the impact of MDJ on obese PCOS patients is still unknown. Hence, the study aims to determine whether MDJ may induce hallmarks of PCOS as new EDCs. The blood samples (33 obese PCOS patients and 30 controls) were collected for metabonomic sequencing. Sequencing results that serum MDJ level was significantly increased in obese PCOS patients, and was closely associated with the clinical phenotype of PCOS. C57BL/6J female mice fed high-fat diets were randomly divided into four groups. The PCOS model was established by subcutaneous injection of dehydroepiandrosterone for 21 days. Different concentrations of MDJ group were gavage of MDJ (60, and 120 mg/kg/d), and the control group was gavage of corn oil, once daily from pregnancy to offspring 16 weeks old. After 16 weeks, different concentrations of MDJ treatment resulted in an irregular estrus cycle and disturbed ovarian development in female mice. Serum TT and insulin resistance levels were increased in the MDJ group. At the cellular level, different concentrations of MDJ (50, and 100 μg/L) intervention mouse-primary-granulosa-cells (mpGCs) and measured supernatant TT levels after 48h. In the mouse ovarian tissue and mpGCs, we found that the expression of key genes for steroid synthesis (Star, Cyp17a1, Hsd3b1, Lhcgr) was increased significantly, while the expression of Cyp19a1 decreased after different concentrations of MDJ treatments. In preliminary experiments, we found that long-term exposure to MDJ during pregnancy and growth can induce PCOS phenotype in C57BL/6J female mice. Ongoing studies will determine how MDJ induces the hallmarks of PCOS and related mechanisms, which may help reveal the pathogenesis of PCOS. Disclosure M.Cai: None. D.Dilimulati: None. Y.Zhang: None. X.Shao: None. S.Qu: None. M.Zhang: None. Funding National Key R&amp;D Program of China (2018YFC1314100); National Natural Science Foundation of China (81601269)

Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Telomere Structure and Function Disorder Mediates Cell Cycle Dysregulation and Apoptosis via c-Myc and Its Upstream Transcription Factors in a Mouse Spermatogonia-Derived (GC-1) Cell Line.

As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors.

From a toxin to an obesogen: a review of potential obesogenic roles of acrylamide with a mechanistic approach.

Obesity and obesity-related disorders such as cancer, type 2 diabetes, and fatty liver have become a global health problem. It is well known that the primary cause of obesity is positive energy balance. In addition, obesity is the consequence of complex gene and environment interactions that result in excess calorie intake being stored as fat. However, it has been revealed that there are other factors contributing to the worsening of obesity. The presence of nontraditional risk factors, such as environmental endocrine-disrupting chemicals, has recently been associated with obesity and comorbidities caused by obesity. The aim of this review was to examine the evidence and potential mechanisms for acrylamide having endocrine-disrupting properties contributing to obesity and obesity-related comorbidities. Recent studies have suggested that exposure to environmental endocrine-disrupting obesogens may be a risk factor contributing to the current obesity epidemic, and that one of these obesogens is acrylamide, an environmental and industrial compound produced by food processing, particularly the processing of foods such as potato chips, and coffee. In addition to the known harmful effects of acrylamide in humans and experimental animals, such as neurotoxicity, genotoxicity, and carcinogenicity, acrylamide also has an obesogenic effect. It has been shown in the literature to a limited extent that acrylamide may disrupt energy metabolism, lipid metabolism, adipogenesis, adipocyte differentiation, and various signaling pathways, and may exacerbate the disturbances in metabolic and biochemical parameters observed as a result of obesity. Acrylamide exerts its main potential obesogenic effects through body weight increase, worsening of the levels of obesity-related blood biomarkers, and induction of adipocyte differentiation and adipogenesis. Additional mechanisms may be discovered. Further experimental studies and prospective cohorts are needed, both to supplement existing knowledge about acrylamide and its effects, and to clarify its established relationship with obesity and its comorbidities.

Effect of endocrine disrupting chemicals on early disease course in Multiple sclerosis (P5-3.004)

<h3>Objective:</h3> Analyze whether endocrine disrupting chemicals (EDCs) correlate with initiation of Multiple sclerosis (MS) in females <h3>Background:</h3> MS is the most common neuroinflammatory disease with a female predominant ratio of 3:1. Sex hormones are implicated, as most pediatric MS cases occur after puberty, and pregnancy is protective against disease activity. EDCs including phenols, parabens, and phthalates are found ubiquitously in the modern lifestyle. They interfere with natural hormone homeostasis in the body via estrogen receptor signaling. This study focuses on whether exposure to EDCs affect MS initiation. <h3>Design/Methods:</h3> 30 female patients were recruited from the Brigham MS Center. Enrollment criteria included diagnosis with MS within the past 5 years, and consent to provide a blood and urine sample and completed a questionnaire about potential EDC exposures. Exclusion criteria were intravenous steroids in the past 30 days. Samples were analyzed by NSF International (Ann Arbor, Michigan) by LC-MS for phenols, parabens, and phthalates. Statistical results were obtained using R. <h3>Results:</h3> We find that females with higher levels of the phthalates mECPP and mEOHP had higher annualized relapse rates (ARR) from onset of disease (Spearman coefficient, R=0.55, p=0.0014; R=0.65, p=7.8e-05). mECPP and mEOHP levels also correlated with increased number of T2 lesions on MRI (R=0.51, p=0.0033; R=0.57, p=8e-04). mECPP levels were inversely correlated with fish intake (R=−0.38, p=0.02. mEOHP was non-significantly inversely correlated with fish intake (R=−0.30, p=0.06). None of the EDCs analyzed were correlated with use of dishwashers, personal care products, or exposure to microplastics. <h3>Conclusions:</h3> Higher serum levels of phthalates mECPP and mEOHP are correlated with increased lesion burden and disease activity in female MS patients within the first five years of disease onset. Fish intake was inversely correlated with serum levels of these phthalates. This study highlights how diet and exposures to environmental EDCs might partly explain sex differences in disease course in MS. <b>Disclosure:</b> Dr. Chuang has nothing to disclose. Ms. Feldman has nothing to disclose. The institution of Mr. Healy has received research support from Analysis Group. The institution of Mr. Healy has received research support from Bristol-Myers Squibb. The institution of Mr. Healy has received research support from Verily Life Sciences. The institution of Mr. Healy has received research support from Novartis. The institution of Mr. Healy has received research support from Merck Serono. The institution of Mr. Healy has received research support from Genzyme. Shrishti Saxena has nothing to disclose. Ms. Sanon has received personal compensation for serving as an employee of Brigham and Women’s Hospital . Ms. Saraceno has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cumming Foundation. The institution of Ms. Saraceno has received research support from I-Mab Biopharma. Dr. Chitnis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Chitnis has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche-Genentech. Dr. Chitnis has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Academic CME. The institution of Dr. Chitnis has received research support from Novartis. The institution of Dr. Chitnis has received research support from Sanofi. The institution of Dr. Chitnis has received research support from Octave.

Bisphenol A prevents MCF-7 breast cell apoptosis via the inhibition of progesterone receptor transactivation.

2,2-Bis(4-hydroxyphenyl)propane (bisphenol A; BPA) is an environmental endocrine-disrupting chemical. It mimics the effects of estrogen at multiple levels by activating estrogen receptors (ERs); however, BPA also affects the proliferation of human breast cancer cells independent of ERs. Although BPA inhibits progesterone (P4) signaling, the toxicological significance of its effects remain unknown. Tripartite motif-containing 22 (TRIM22) has been identified as a P4-responsive and apoptosis-related gene. Nevertheless, it has not yet been established whether exogenous chemicals change TRIM22 gene levels. Therefore, the present study investigated the effects of BPA on P4 signaling and TRIM22 and TP53 expression in human breast carcinoma MCF-7 cells. In MCF-7 cells incubated with various concentrations of P4, TRIM22 messenger RNA (mRNA) levels increased in a dose-dependent manner. P4 induced apoptosis and decreased viability in MCF-7 cells. The knockdown of TRIM22 abolished P4-induced decreases in cell viability and P4-induced apoptosis. P4 increased TP53 mRNA expression and p53 knockdown decrease the basal level of TRIM22 and P4 increased TRIM22 mRNA expression independent of p53 expression. BPA attenuated P4-induced increases in the ratio of cell apoptosis in a concentration-dependent manner, and the P4-induced decreases in cell viability was abolished in the presence of 100 nM and higher BPA concentrations. Furthermore, BPA inhibited P4-induced TRIM22 and TP53 expression. In conclusion, BPA inhibited P4-induced apoptosis in MCF-7 cells via the inhibition of P4 receptor transactivation. TRIM22 gene has potential as a biomarker for investigating the disruption of P4 signaling by chemicals.

Prenatal BPA exposure disrupts male reproductive functions by interfering with DNA methylation and GDNF expression in the testes of male offspring rats.

BPA is a ubiquitous environmental endocrine-disrupting chemical, and maternal exposure to BPA is associated with impaired male reproductive functions; however, the mechanisms remain to be elucidated. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in maintaining normal spermatogenesis and fertility. However, the effect of prenatal BPA exposure on GDNF expression and its mechanism in the testis has not been reported. In this study, pregnant Sprague-Dawley rats were respectively exposed to 0, 0.05, 0.5, 5, and 50 mg/kg/day BPA via oral gavage from gestational day (GD) 5 to GD 19, with 6 pregnant rats in each group. ELISA, histochemistry, real-time PCR, western blot, and methylation-specific PCR (MSP) were used to detect the sex hormone levels, testicular histopathology, mRNA and protein expression of DNA methyltransferases (DNMTs) and GDNF, and the promoter methylation of Gdnf in the testes of male offspring at postnatal day (PND) 21 and PND 56. Prenatal BPA exposure increased body weight; decreased sperm counts and serum levels of testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH); and induced testicular histological damage, which indicated the damage of male reproductive function. Prenatal BPA exposure also upregulated Dnmt1 in 5 mg/kg group and Dnmt3b in 0.5 mg/kg group, but down-regulated Dnmt1 in 50 mg/kg group at PND 21. At PND 56, Dnmt1 was significantly increased in 0.05 mg/kg group but decreased in 0.5, 5, and 50 mg/kg groups, Dnmt3a was decreased, and Dnmt3b was markedly increased in 0.05 and 0.5 mg/kg groups but decreased in 5 and 50 mg/kg groups. The mRNA and protein expression levels of Gdnf were decreased markedly in 0.5 and 50 mg/kg groups at PND 21. And the methylation level of Gdnf promoter was significantly increased in 0.5 mg/kg group, but decreased in 5 and 50 mg/kg groups at PND 21. In conclusion, our study indicates that prenatal BPA exposure disrupts male reproductive functions, interferes with the expression of DNMTs, and decreases Gdnf expression in the testes of male offspring. Gdnf expression may be regulated by DNA methylation; however, the detailed mechanism needs to be further investigated.

Atrazine induces phagocytotic dysfunction of microglia depends on nucleocytoplasmic translocation of acetylated HMGB1

Atrazine (ATR) is a widely applied herbicide which was named an environmental endocrine disrupting chemical (EDC). Increasing evidence indicates ATR causes neurotoxic effects resulting in central nervous system (CNS) disease. As the primary immunocytes in the CNS, microglia cells carry out their phagocytosis to maintain the CNS microenvironment by preventing damage from healthy cells. However, the mechanism in which ATR affects the phagocytic function of microglia remains unclear. The present study was designed to investigate the effect of ATR on the phagocytosis of microglia. BV-2 cells and primary microglia selected as microglial models in which BV-2 cells were administrated by ATR at different concentrations (0, 4, 8, 16 μM) for 24 h. Results demonstrated ATR dose-dependently increased the expression of ionized calcium binding adapter molecule 1 (Iba-1), indicating that microglia were activated. Microglial phagocytotic activity induced by ATR fluctuated at the different time points, accompanied by fluctuations in membrane receptor MERTK and cytoplasmic lysosomal marker LAMP1 (two markers related to cell phagocytosis). In this period, the expression of iNOS gradually increased. A mechanistic study further demonstrated that the translocation of High Mobility Group Protein-B1 (HMGB1) from nucleus to cytoplasm in the BV-2 and primary microglial cells induced by ATR, and the process showed a positive correlation with phagocytosis activity of BV-2 cells induced by ATR (r = 0.8030, P = 0.05; α = 0.1). ATR was also shown to spur the acetylation of HMGB1 by breaking the balance between acetylase P300 and deacetylase SIRT1. Unexpectedly, the inhibition of acetylating HMGB1 by resveratrol (Res) was effectively retained by HMGB1 in the nucleus, reversed the SIRT1 and MERTK expression, and enhanced the phagocytosis activity in BV-2 cells. Our results suggested that ATR exposure influenced microglial phagocytosis by acetylating HMGB1 further translocated it in the nucleoplasm.

Quantum Chemical GA-MLR, Cluster Model, and Conceptual DFT Descriptors Studies on the Binding Interaction of Estrogen Receptor Alpha with Endocrine Disrupting Chemicals

In the present study, the predication of the binding affinity (log RBA) of estrogen receptor alpha with three categories of environmental endocrine disrupting chemicals (EDCs), namely, PCB, phenol, and DDT, is performed by the quantum chemical genetic algorithm multiple linear regression (GA-MLR) method. The result of the optimal model indicates that log RBA increases with increasing the electrophilicity and hydrophobicity of EDCs. However, by using the quantum chemical cluster model approach, the modeling results reveal that electrostatic interaction and hydrogen bonding play a significant role. The chemical reactivity descriptors calculated based on the conceptual density functional theory also indicate that the binding mechanism of charge-controlled interaction is superior to that of frontier-controlled interaction.