Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 7, 2022

Bisphenol A (BPA) is a monomer that is widely used in the manufacturing of polycarbonate plastics (including storage plastics and baby bottles) and is considered to be one of the most widely used synthetic compounds in the manufacturing industry. Exposure to BPA mainly occurs after oral ingestion and results from leaks into food and water from plastic containers. According to epidemiological data, exposure is widespread and estimated to occur in 90% of individuals. BPA exhibits pleiotropic and estrogen-like effects; thus, it is considered an endocrine-disrupting chemical. A growing body of evidence highlights the role of BPA in modulating immune responses and signaling pathways, which results in a proinflammatory response by enhancing the differential polarization of immune cells and cytokine production profile to one that is consistent with proinflammation. Indeed, epidemiological studies have uncovered associations between several autoimmune diseases and BPA exposure. Data from animal models provided consistent evidence, which highlighted the role of BPA in the pathogenesis, exacerbation, and perpetuation of various autoimmune phenomena including neuroinflammation in the context of multiple sclerosis, colitis in inflammatory bowel disease, nephritis in systemic lupus erythematosus, and insulitis in type 1 diabetes mellitus. Owing to the widespread use of BPA and its effects on immune system dysregulation, a call for careful assessment of patients’ risks and public health measures are needed to limit exposure and subsequent deleterious effects. The purpose of this study is to explore the autoimmune triggering mechanisms and present the current literature supporting the role of BPA in the pathogenesis of autoimmune diseases.

Background: Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds deriving from different human activities and are widely spread into the environment, contributing to indoor and outdoor pollution. EDCs may be conveyed by food and water consumption and skin, airways, placental, and breastfeeding. Upon entering the circulation, they can interfere with endocrine system homeostasis by several mechanisms. Aim: In this narrative review, the authors overviewed the leading mechanisms by which EDCs interact and disrupt the endocrine system, leading to possible human health concerns. Results: The leading mechanisms of EDCs-related toxicity have been illustrated in in vitro studies and animal models and may be summarized as follows: receptor agonism and antagonism; modulation of hormone receptor expression; interference with signal transduction in hormone-responsive cells; epigenetic modifications in hormone-producing or hormone-responsive cells; interference with hormone synthesis; interference with hormone transport across cell membranes; interference with hormone metabolism or clearance; interference with the destiny of hormone-producing or hormone- responsive cells. Discussion: Despite these well-defined mechanisms, some limitations do not allow for conclusive assumptions. Indeed, epidemiological and ecological studies are currently lacking and usually refer to a specific cluster of patients (occupational exposure). Methodological aspects could further complicate the issue since these studies could require a long time to provide useful information. The lack of a real unexposed group in environmental conditions, possible interference of EDCs mixture on biological results, and unpredictable dose-response curves for some EDCs should also be considered significant limitations. Conclusion: Given these limitations, specific observational and long-term studies are needed to identify at-risk populations for adequate treatment of exposed patients and effective prevention plans against excessive exposure to EDCs.

The male reproductive system is exposed to a great number of chemical substances which can interfere with the normal hormonal milieu and reproductive function; these are called endocrine disruptors (EDs). Despite a growing number of studies evaluating the negative effects of EDs, their production is continuously growing although some of them have been prohibited. The prevalence of poor semen quality, hypospadias, cryptorchidism, and testicular cancer has increased in the last decades, and recently, it has been postulated that these could all be part of a unique syndrome called testicular dysgenesis syndrome. This syndrome could be related to exposure to a number of EDs which cause imbalances in the hormonal milieu and oestrogenic over-exposure during the foetal stage. The same EDs can also impair spermatogenesis in offspring and have epigenetic effects. Although studies on animal and in vitro models have raised concerns, data are conflicting. However, these studies must be considered as the basis for future research to promote male reproductive health.

Background: Endocrine Disrupting Chemicals (EDCs) are ubiquitous and may significantly contribute to environmental pollution and contamination in humans and wildlife. Ecological pollutants could interfere with bone homeostasis through different mechanisms, including hormonal imbalance, direct osteoblast toxicity, and enhancement of osteoclasts activity, leading to either osteopenia or osteoporosis. Among these chemicals, bisphenols, dioxins, polycyclic aromatic hydrocarbons, polychlorobiphenyls, poly- and perfluoroalkyl, phthalates, parabens, organotins, and cadmium may play a role in the bone disruption. Methods: Authors searched PubMed/MEDLINE, ISI-web of knowledge, and Google scholar databases for medical subject headings terms and free-text words related to the classes mentioned above of chemicals and bone metabolism and remodeling for better clarifying and understanding the main mechanisms of bone disruption. Results: Several EDCs act as xeno-estrogens. Considering that estrogens play a significant role in regulating bone remodeling, most of these chemicals generate hormonal imbalance with possible detrimental consequences on bone tissue structure and its mechanical and non-mechanical properties. Discussion: Much evidence about bone disruptors was obtained from in vitro studies or animal models with equivocal results. Besides, a few data have been acquired from humans, and most of these data focused on the impact of EDCs on bone mineral density without considering their influence on long-term fracture risk. Moreover, humans may be exposed to a mixture of EDCs, and the final effect on bone metabolism might be attributable to either synergistic or antagonist effects. Age of first exposure, cumulative exposure over time, and the usually observed non-monotonic dose-response curve for EDCs should be considered as other essential variables influencing bone metabolism's final effect. Conclusion: Given these variables, observational studies are needed to analyze this issue for ecological purposes better and preserve bone health.

Background: Bisphenol A (BPA), an important industrial material widely applied in daily products, is considered an endocrine-disrupting chemical that may adversely affect humans. Growing evidence has shown that intestinal bacterial alterations caused by BPA exposure play an important role in several local and systemic diseases. Aims: Finding evidence that BPA-induced alterations in gut microbiota composition and activity may perturb its role on human health. Results: Evidence from several experimental settings shows that both low and high doses of BPA interfere with the hormonal, homeostatic, and reproductive systems in animals and humans. Moreover, it has recently been classified as an environmental obesogenic, with metabolic-disrupting effects on lipid metabolism and pancreatic b-cell functions. Several evidence characterizes PBA as an environmental contributor to type II diabetes, metabolic syndromes, and obesity. However, the highest estimates of the exposure derived from foods alone or in combination with other sources are 3 to 5 times below the new tolerable daily intake (TDI) value, today reduced by the European Food Safety Authority (EFSA) experts from 50 micrograms per kilogramme of bodyweight per day (μg/kg bw/day) to 4 μg/kg bw/day. Conclusion: Considering estimates for the total amount of BPA that can be ingested daily over a lifetime, many International Health Authorities conclude that dietary exposure of adult humans to BPA does not represent a risk to consumers' health, declaring its safety due to very-low established levels in food and water and any appreciable health risk.

The population worldwide is largely exposed to bisphenol A (BPA), a commonly used plasticizer, that has a similar molecular structure to endogenous estrogens. Therefore, it is able to influence physiological processes in the human body, taking part in pathophysiology of various endocrinopathies, as well as, cardiovascular, neurological and oncological diseases. BPA has been found to affect the immune system, leading to the development of autoimmunity and allergies, too. In the last few decades, the prevalence of autoimmune diseases has significantly increased that could be explained by a rising exposure of the population to environmental factors, such as BPA. BPA has been found to play a role in the pathogenesis of systemic autoimmune diseases and also organ-specific autoimmunity (thyroid autoimmunity, diabetes mellitus type 1, myocarditis, inflammatory bowel disease, multiple sclerosis, encephalomyelitis etc), but the results of some studies still remain controversial, so further research is needed.

Background and Objectives: The purposes of this review are to promote better use of existing knowledge of marine pollutants, especially endocrine-disrupting compounds (EDCs), and to draw attention to the slow progression of the research on the influence of those compounds on arginine vasotocin/isotocin system (AVT/IT) in fish. EDCs are leading to the degradation of fish habitats, reducing their spawning potential and possibly their population parameters (e.g. growth, maturation), by preventing fish from breeding and rebuilding their populations. Therefore, searching for new welfare indicators such as AVT and IT and developing research procedures mimicking environmental conditions using a versatile fish model is extremely important. Discussion: Fish species such as zebrafish (Danio rerio) and round goby (Neogobius melanostomus) can be recommended as very suitable models for studying estrogenic EDCs on the AVT/IT system and other hormones involved in the neuroendocrine regulation of physiological processes in fish. Conclusion: These studies would not only improve our understanding of the effects of EDCs on vertebrates but could also help safeguard the well-being of aquatic and terrestrial organisms from the harmful effects of these compounds.

Background: Endocrine disrupting chemicals (EDCs) are found in plastics, personal care products, household items, and other consumer goods. Risk assessments are intended to characterize a chemical’s hazards, identify the doses at which adverse outcomes are observed, quantify exposure levels, and then compare these doses to determine the likelihood of risk in a given population. There are many problems with risk assessments for EDCs, allowing people to be exposed to levels that are later associated with serious health outcomes in epidemiology studies. Objective: In this review, we examine issues that affect the evaluation of EDCs in risk assessments (e.g., use of insensitive rodent strains and absence of disease-oriented outcomes in hazard assessments; inadequate exposure assessments). We then review one well-studied chemical, Bisphenol A (BPA; CAS #80-05-7) an EDC found in plastics, food packaging, and other consumer products. More than one hundred epidemiology studies suggest associations between BPA exposures and adverse health outcomes in environmentally exposed human populations. Results: We present support for the use of systematic review methodologies in the evaluation of BPA and other EDCs. Systematic reviews would allow studies to be evaluated for their reliability and risk of bias. They would also allow all data to be used in risk assessments, which is a requirement for some regulatory agencies. Conclusion: Systematic review methodologies can be used to improve evaluations of BPA and other EDCs. Their use could help to restore faith in risk assessments and ensure that all data are utilized in decision-making. Regulatory agencies are urged to conduct transparent, well-documented and proper systematic reviews for BPA and other EDCs.

Background: Foam cells, mainly derived from monocytes-macrophages, contain lipid droplets essentially composed of cholesterol in their cytoplasm. They infiltrate the intima of arteries, contributing to the formation of atherosclerotic plaques. Pathogenesis: Foam cells damage the arterial cell wall via the release of proinflammatory cytokines, free radicals, and matrix metalloproteinases, enhancing the plaque size up to its rupture. Therapy: A correct dietary regimen seems to be the most appropriate therapeutic approach to minimize obesity, which is associated with the formation of foam cells. At the same time, different types of antioxidants have been evaluated to arrest the formation of foam cells, even if the results are still contradictory. In any case, a combination of antioxidants seems to be more efficient in the prevention of atherosclerosis.

Periodontitis is an oral chronic inflammatory condition affecting the adult population worldwide. Many microorganisms act as initiators for inducing inflammatory immune responses, which participate in the destruction of connective tissue surrounding the teeth, thereby resulting in tooth loss. Cytokines may have indispensable roles in its pathogenesis by enhancing inflammatory and immune responses. Cytokines can affect the functions of some cells of different tissues, such as the cells of the pancreas, liver, and adipose tissues. Evidence suggests that periodontitis is associated with metabolic disorders like liver cirrhosis, obesity, and diabetes mellitus. Hence, this review focused on determining how cytokines can participate in the correlation of periodontitis with metabolic disorders.

Background: Previous studies have shown that endoplasmic reticulum (ER) stress is related to the apoptosis in the development of diabetic nephropathy (DN) and thalidomide (Thd) has renalprotective effects by suppressing inflammation and proliferation of MCs in DN. However, the effect of Thd on the apoptosis of MCs in DN remains largely unclear. The present research is designed to explore the effect of Thd on apoptosis in DN and the related mechanisms. Objective: The study is designed to examine the effect and mechanism of Thd on apoptosis in type 2 diabetic mice and high glucose (HG)-induced MCs. Methods: We first evaluated the ER stress markers and apoptosis-related proteins with the treatment of Thd in type 2 diabetic mice and MCs in vitro under HG conditions. MTT assay was used to assess cell viability. Additionally, we evaluated the effect of Thd treatment upon MC apoptosis through flow cytometry. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate genes and protein expression related to ER stress and apoptosis. Results: The levels of blood urea BUN, CREA, Urine albumin, and UACR in diabetic mice were observed to be significantly reduced after 8 weeks of intervention with Thd. And also, there were upregulated glucose-regulated protein 78 (GRP78), Caspase-12, and downregulated B-cell lymphoma 2 (Bcl-2) in glomeruli of DN mice. In vitro, compared with the HG group, MC apoptosis reduced dramatically with Thd treatment along with upregulation of Bcl-2 and downregulation of Bax. At the same time, ER stress markers GRP78, C/EBP homologous protein (CHOP), and Caspase-12 were also mitigated following the Thd treatment. Conclusion: The present study indicates that Thd might reduce the ER stress in DN via downregulating GRP78, CHOP, and Caspase12 expressions, ultimately mitigating MCs apoptosis.