Targets Of Endocrine Disrupting Chemicals Research Articles

A System Biology Approach Reveals New Targets for Human Thyroid Gland Toxicity in Embryos and Adult Individuals.

Compounds of natural or synthetic origin present in personal care products, food additives, and packaging may interfere with hormonal regulation and are called endocrine-disrupting chemicals (EDCs). The thyroid gland is an important target of these compounds. The objective of this study was to analyze public data on the human thyroid transcriptome and investigate potential new targets of EDCs in the embryonic and adult thyroid glands. We compared the public transcriptome data of adult and embryonic human thyroid glands and selected 100 up- or downregulated genes that were subsequently subjected to functional enrichment analysis. In the embryonic thyroid, the most highly expressed gene was PRMT6, which methylates arginine-4 of histone H2A (86.21%), and the downregulated clusters included plasma lipoprotein particles (39.24%) and endopeptidase inhibitory activity (24.05%). For the adult thyroid gland, the most highly expressed genes were related to the following categories: metallothionein-binding metals (56.67%), steroid hormone biosynthetic process (16.67%), and cellular response to vascular endothelial growth factor stimulus (6.67%). Several compounds ranging from antihypertensive drugs to enzyme inhibitors were identified as potentially harmful to thyroid gland development and adult function.

REPRODUCTIVE TOXICOLOGY: The male mammary gland: a novel target of endocrine-disrupting chemicals.

In the past several decades, the incidence of two male breast diseases, gynecomastia and male breast cancer, have increased in human populations. Whereas male breast cancer remains a rare disease, gynecomastia, a condition that arises due to abnormal development and growth of the male breast epithelium, is fairly common. In this review, we present the male mouse mammary gland as a potential model to understand human male breast diseases. Even though the male mouse typically lacks nipples, the male retains a small mammary rudiment with epithelium that is highly sensitive to estrogenic chemicals during the perinatal and peripubertal periods. In just the last few years, our understanding of the biology of the male mouse mammary gland has expanded. Researchers have characterized the complexity and size of the male mammary epithelium across the life course. Studies have documented that the male mouse mammary gland has left-right asymmetric morphologies, as well as asymmetries in the responsiveness of the left and right glands to estrogens. Recent studies have also revealed that the effect of xenoestrogens on the male mammary gland can differ based on the timing of evaluation (prior to puberty, in puberty, and in adulthood) and the administered dose. Based on the available evidence, we argue that there is a strong case that estrogenic chemicals promote the growth of the male mouse epithelium, consistent with human gynecomastia. We also argue that these outcomes should be characterized as adverse effects and should be considered in regulatory decision-making.

Cellular and molecular features of EDC exposure: consequences for the GnRH network.

The onset of puberty and the female ovulatory cycle are important developmental milestones of the reproductive system. These processes are controlled by a tightly organized network of neurotransmitters and neuropeptides, as well as genetic, epigenetic and hormonal factors, which ultimately drive the pulsatile secretion of gonadotropin-releasing hormone. They also strongly depend on organizational processes that take place during fetal and early postnatal life. Therefore, exposure to environmental pollutants such as endocrine-disrupting chemicals (EDCs) during critical periods of development can result in altered brain development, delayed or advanced puberty and long-term reproductive consequences, such as impaired fertility. The gonads and peripheral organs are targets of EDCs, and research from the past few years suggests that the organization of the neuroendocrine control of reproduction is also sensitive to environmental cues and disruption. Among other mechanisms, EDCs interfere with the action of steroidal and non-steroidal receptors, and alter enzymatic, metabolic and epigenetic pathways during development. In this Review, we discuss the cellular and molecular consequences of perinatal exposure (mostly in rodents) to representative EDCs with a focus on the neuroendocrine control of reproduction, pubertal timing and the female ovulatory cycle.

Endocrine disrupting chemicals and COVID-19 relationships: A computational systems biology approach.

Patients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19. To explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied. As a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis. We found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising. Pathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.

SAT-710 Comparative Histopathology of Endocrine Glands in Phthalate Exposed Male Wistar Rats Unveil the Vulnerability of Adrenal Gland and Augmented by Molecular Docking

Limited research has been conducted on adrenal gland as a target of endocrine-disrupting chemicals (EDCs). Moreover, studies on steroidogenesis as the target of EDCs has also attracted lesser attention compared to other metabolic pathways. We studied the effects of two extensively used phthalate esters viz., di-ethyl hexyl phthalate (DEHP) and di-butyl phthalate (DBP) on the adrenal gland in Wistar rats and checked its susceptibility against the exposure of these extensively used phthalates categorized as EDCs. Male rats were divided into seven groups (n = 6). Group I (control) received only corn oil (as a vehicle). Group II, III and IV were treated daily with DEHP at the dose of 250, 750 and 1500 mg/kg-BW respectively per os for 14 days. Group V, VI and VII were treated with a daily dose of DBP 100, 500 and 1000 mg/kg-BW respectively per os for 14 days. The comparative histological observation of endocrine glands i.e., pituitary, pineal, thyroid, parathyroid, adrenal gland and testes unveil that changes in adrenal gland towards the DEHP and DBP were more remarkable compared to other endocrine glands. Glucocorticoid biosynthesis pathway in the adrenal gland was analyzed by molecular docking of DEHP and DBP with the enzyme proteins involved in the pathway using Maestro Schrodinger 9.4 software. It showed the potential of DEHP and DBP to inhibit these proteins comparable to the known inhibitors of enzymes involved. The present study used a novel approach of in silico and in vivo to elucidate the sensitivity of adrenal gland towards EDCs through the analysis of the sensitivity of adrenal steroidogenesis on exposure to two widely distributed phthalates with environmental and human health risk potential.

Diets contaminated with Bisphenol A and Di-isononyl phtalate modify skeletal muscle composition: A new target for environmental pollutant action

In the last years, an increasing number of studies reported that food pollution represents a significant route of exposure to environmental toxicants, able to cause mild to severe food illnesses and health problems, including hormonal and metabolic diseases. Pollutants can accumulate in organisms and biomagnify along the food web, finally targeting top consumers causing health and economic problems. In this study, adults of gilthead sea bream, Sparus aurata, were fed with diets contaminated with Bisphenol A (BPA) (4 and 4000 μg BPA kg−1 bw day−1) and Di-isononyl phthalate (DiNP) (15 and 1500 μg DiNP kg−1 bw day−1), to evaluate the effects of the contamination on the muscle macromolecular composition and alterations of its texture.The analysis conducted in the muscle using infrared microspectroscopy, molecular biology and biochemical assays, showed, in fish fed BPA contaminated diets, a decrease of unsaturated lipids and an increase of triglycerides and saturated alkyl chains. Conversely, in fish fed DiNP, a decrease of lipid content, caused by a reduction of both saturated and unsaturated chains and triglycerides was measured. Protein content was decreased by both xenobiotics evidencing a novel macromolecular target affected by these environmental contaminants. In addition, in all treated groups, proteins resulted more phosphorylated than in controls. Calpain and cathepsin levels, orchestrating protein turnover, were deregulated by both xenobiotics, evidencing alterations of muscle composition and texture. In conclusion, the results obtained suggest the ability of BPA and DiNP to modify the muscle macromolecular building, advising this tissue as a target of Endocrine-Disrupting Chemicals (EDCs) and providing a set of biomarkers as possible monitoring endpoints to develop novel OEDC test guidelines.

Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes.

Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function. EDCs can affect multiple cellular processes, including some related to energy production and utilization, leading to alterations in energy homeostasis. Mitochondria are primarily implicated in cellular energy conversion, although they also participate in other processes, such as hormone secretion and apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired lipid oxidation and increased oxidative stress has been linked to insulin resistance and type 2 diabetes. Herein, we review the main mechanisms whereby metabolism-disrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause mitochondrial dysfunction, thus contributing to the establishment of insulin resistance and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis and dynamics, excessive reactive oxygen species production and activation of the mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking MDCs to type 2 diabetes development.

Effects of Short-term Exposure to the DDT Metabolite p,p′-DDE on Bone Tissue in Male Common Frog (Rana temporaria)

Experimental studies as well as studies in free-ranging animals have shown that endocrine-disrupting chemicals (EDCs) impair bone tissue composition and strength. The aim of the present study was to expand our studies on bone tissue in a new group of animals by investigating whether bone tissue in frogs is an additional potential target of EDCs. Adult male European common frogs (Rana temporaria) were divided into 5 groups (n = 20) and injected (sc, single injection) with p,p′-DDE, a total dose of 0.01, 0.1, 1, or 10 mg of p,p′-DDE/kg body weight, respectively. A control group was treated with the vehicle (corn oil). Two weeks after injection the frogs were euthanized and samples taken. The diaphysis of the excised left femur was scanned using peripheral quantitative computed tomography (pQCT) and cortical variables, such as cortical bone mineral density (BMD), cortical cross-sectional area (CSA), and periosteal circumference, were determined. In addition, biomechanical three-point bending of the bones was conducted, with the load being applied to the same point as where the pQCT measurement was performed. The results from the pQCT measurements show that bone tissue in male frogs exposed to p,p′-DDE is negatively affected. A significant decrease in cortical BMD at the diaphysis was observed in frogs exposed to 1 mg p,p′-DDE. However, the biomechanical testing of the bones showed no significant differences between exposed and control group. Although this is the only study performed to date examining the possible relationships between EDCs and negative effects on frog bones, it supports both previous experimental findings in rodents and findings in free-ranging animals.

The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals

Various chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms. Increasingly, the enzymes involved in the steroid biosynthesis pathway are being recognized as important targets for the actions of various endocrine-disrupting chemicals. Interferences with steroid biosynthesis may result in impaired reproduction, alterations in (sexual) differentiation, growth, and development and the development of certain cancers. Steroid hormone synthesis is controlled by the activity of several highly substrate-selective cytochrome P450 enzymes and a number of steroid dehydrogenases and reductases. Particularly aromatase (CYP19), the enzyme that converts androgens to estrogens, has been the subject of studies into the mechanisms by which chemicals interfere with sex steroid hormone homeostasis and function, often related to (de)feminization and (de)masculinazation processes. Studies in vivo and in vitro have focussed on ovarian and testicular function, with less attention given to other steroidogenic organs, such as the adrenal cortex. This review aims to provide a comprehensive overview of the state of knowledge regarding the mechanisms by which chemicals interfere with the function of steroidogenic enzymes in various tissues and organisms. The endocrine toxicities and mechanisms of action related to steroidogenesis of a number of classes of drugs and environmental contaminants are discussed. In addition, several potential in vitro bioassays are reviewed for their usefulness as screening tools for the detection of chemicals that can interfere with steroidogenesis. Analysis of the currently scattered state of knowledge indicates that still relatively little is known about the underlying mechanisms of interference of chemicals with steroidogenesis and their potential toxicity in steroidogenic tissues, neither in humans nor in wildlife. Considerably more detailed and systematic research in this area of (endocrine) toxicology is required for a better understanding of risks to humans and wildlife.

The effects of endocrine disrupting chemicals on the ovary.

Endocrine disrupting chemicals (EDCs) are natural or synthetic chemicals that mimic, enhance, or inhibit endogenous hormones. In this article, we review possible targets of EDCs within the ovary and explore whether EDCs may be acting as estrogen mimics, interfering with apoptosis, altering cell signaling pathways, or affecting estrogen metabolism. Though the study of EDCs has remained controversial, it is important to study them because our society continues to release large amounts of industrial chemicals into our environment and uncovering the mechanisms of action may lead to treatments of any potential adverse effects. In addition, studying how EDCs affect the ovary may lead to serendipitous discoveries about ovarian function and dysfunction. Finally, understanding the science behind endocrine disruption may influence the political and regulatory handling of EDCs.