Endocrine disruption in metabolic disorders: Biomarkers and therapeutic targets.

The worldwide prevalence of obesity and metabolic disease is increasing at an exponential rate and current projections provide no indication of relief. This growing burden of obesity-related metabolic disorders, including type 2 diabetes mellitus (T2DM), highlights the importance of identifying how lifestyle choices, genetics and physiology play a role in metabolic disease and place obese individuals at a greater risk for obesity-related complications including insulin resistance (IR). This increased risk of IR, which is characterized by a decreased response to insulin in peripheral tissues including adipose tissue (AT) and liver, is associated with a chronic, low grade inflammatory state; however, the causative connections between obesity and inflammation remains in question. Experimental evidence suggests that adipocytes and macrophages can profoundly influence obesity-induced IR because adipocyte dysfunction leads to ectopic lipid deposition in peripheral insulin sensitive tissues, and obese AT is characterized by increased local inflammation and macrophage and other immune cell populations. Attempts to delineate the individual roles of macrophage-derived proinflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), have demonstrated causative roles in impaired systemic insulin sensitivity, adipocyte function and hepatic glucose and lipid metabolism in obese animal models. Thus, the attenuation of macrophage-derived inflammation is an evolving area of interest to provide insight into the underlying mechanism(s) leading to obesity-induced IR. Thus, in the first chapter of this thesis, I describe experiments to refine the current paradigm of obesity-induced AT inflammation by combining gene expression profiling

Simple SummaryMulti-omics has become a crucial tool in cancer biomarker discovery over the last decade, including for prostate cancer. This approach integrates data from various biological layers, enhancing our understanding of complex, heterogeneous cancers. Multi-omics accelerates precision medicine by identifying new biomarkers and therapeutic targets, potentially improving treatment options for advanced prostate cancer patients. This review discusses traditional prostate cancer biomarkers and highlights recent single-omics and multi-omics advances that have improved clinical diagnostic and prognostic capabilities.Prostate cancer remains a significant health challenge, being the most prevalent non-cutaneous cancer in men worldwide. This review discusses the critical advancements in biomarker discovery using single-omics and multi-omics approaches. Multi-omics, integrating genomic, transcriptomic, proteomic, metabolomic, and epigenomic data, offers a comprehensive understanding of the molecular heterogeneity of prostate cancer, leading to the identification of novel biomarkers and therapeutic targets. This holistic approach not only enhances the specificity and sensitivity of prostate cancer detection but also supports the development of personalized treatment strategies. Key studies highlighted include the identification of novel genes, genetic mutations, peptides, metabolites, and potential biomarkers through multi-omics analyses, which have shown promise in improving prostate cancer management. The integration of multi-omics in clinical practice can potentially revolutionize prostate cancer prognosis and treatment, paving the way for precision medicine. This review underscores the importance of continued research and the application of multi-omics to overcome current challenges in prostate cancer diagnosis and therapy.

Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor (BDNF) gene that results in the substitution of a valine with a methionine at codon 66 (Val66Met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of cluster of differentiation 36 (CD36), a multifunctional receptor implicated in obesity and insulin resistance, in WT mice and mice with the BDNF Val66Met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese WT mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was abrogated in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the Val66Met variant in both alleles (BDNFM/M) fed a high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNFM/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extremely obese BDNFM/M mice compared with the WT mice. The study demonstrated a link between BDNF Val66Met and elevated CD36 expression and suggested that CD36 inhibition may be a potential strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.

Endocrine disruptors or endocrine-disrupting chemicals (EDCs) represent a highly heterogeneous group of molecules found in the environment or in consumer products. Toxicology and epidemiology studies have suggested the involvement of diverse EDCs in an increasing number of metabolic disorders, including insulin resistance (IR) and IR-related co morbidities, such as obesity, type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Nonalcoholic fatty liver disease (NAFLD), another IR related condition, is emerging as a significant public health concern, affecting 30-45% of the general population in the Western world. To evaluate whether EDCs may also play a role in the pathogenesis of NAFLD, we reviewed the literature on well-studied EDCs, such as dioxins, bisphenol A, phthalates and other persistent organic pollutants, in relation to pathways that might contribute to the pathogenesis of fatty liver / NAFDL. Certain EDCs may be responsible for inducing alterations similar to those encountered in NAFLD either directly through a hepatotoxic effect and/or indirectly by triggering hepatic and systematic IR. Considering these effects, which act in concert with the effects of the epidemics of obesity and T2DM, EDCs may play a significant role in the pathogenesis of fatty liver, thereby increasing the prevalence of NAFLD worldwide. Translational studies and clinical trials investigating the association between EDCs and NAFLD are required to confirm and extent these studies.

Getting Big on BPA: Role for BPA in Obesity?

On 19 February 2013, the United Nations Environment Programme (UNEP) and the World Health Organization (WHO) released The State of the Science of Endocrine Disrupting Chemicals - 2012 (WHO/UNEP 2013), an extensive update of an earlier document, Global Assessment of the State-of-the-Science of Endocrine Disruptors (International Programme on Chemical Safety 2002). Over the past decade there have been significant advances in our understanding of endocrine disrupting chemicals (EDCs): their numbers, mechanisms of action, biological effects, and impacts on human and wildlife health. First, as described in the new report (WHO/UNEP 2013), the convergence of wildlife, laboratory animal, and epidemiology data suggests a greater role for EDCs in disease, even more than was predicted just 10 years ago. Taking the animal and human evidence together, the report demonstrates a strong likelihood that exposure to EDCs during fetal life and/or puberty plays a role in the proliferation of male and female reproductive problems, endocrine-related cancers, infections, asthma, obesity, diabetes, and behavioral and learning disorders, including attention deficit/hyperactivity disorder (ADHD). The incidences of these conditions have increased significantly not only in the United States but across the globe. Because genes do not change fast enough to explain this increase, environ-mental causes must be involved. The environmental contribution to disease is estimated to be 24–33% of the global disease burden (Smith et al. 1999). Although it is challenging to address the role of the environ-ment in disease, there is also a tremendous opportunity to improve human health by identifying environ-mental elements that affect public health. The recog-nition of these challenges and opportunities, along with the fact that many diseases are associated with the endocrine system (e.g., infertility, diabetes, breast and prostate cancer) has led to the focus on EDCs. Second, it is now accepted that development (in utero and the first years of life) is a very sensitive time for EDC-induced health effects (Kortenkamp et al. 2011). Over the last 10 years, the focus of EDC research has shifted from investigating adult exposure and disease outcomes to examining develop-mental exposure and later-life disease outcomes. This latter approach is now considered the most appropriate approach for most endocrine-related diseases/disorders (U.S. Environmental Protection Agency 2012). Third, identifying those chemicals with endocrine activity from all the chemicals used and released worldwide is a major challenge, and we are likely assessing only the “tip of the iceberg.” Hundreds of chemicals, as well as persistent organic pollutants, have been identified as EDCs. EDCs are not uniform: They have very different properties, sources, and fates in the environment. Although it may be possible to trace high production volume chemicals, numerous additives and process chemicals are not traceable. Adding to this complexity are the unintended and possibly unknown by-products of chemical manu-facturing, including chemicals resulting from combustion, toxicants resulting from the transformation of chemicals after their release into the environment, and internally created metabolites, all of which may increase the number of potential exposures to EDCs in our environment. EDCs likely affect all hormonal systems that control the develop-ment and function of reproductive organs, regulation of metabo-lism, and satiety. Recent research has shown that EDCs also affect physiological systems that control fat develop-ment, weight gain, and glucose levels (Thayer et al. 2012). Finally, as noted in the new WHO/UNEP report (WHO/UNEP 2013), EDCs are a global problem and will require global solutions. EDCs have contaminated the world via the natural flow of air and water. Several hundred EDCs have been measured in humans and wildlife, even in remote places such as the Arctic. Thus, it is now impossible to examine an -unexposed population anywhere on Earth. To improve health, environmental health scientists and toxicologists need to work more closely with colleagues in endocrinology, genetics, developmental biology, epigenetics, and clinical medicine to bring EDC research into the mainstream of science. These and other important topics related to EDCs and their effects are detailed in The State of the Science of Endocrine Disrupting Chemicals - 2012 (WHO/UNEP 2013). I commend WHO/UNEP and the scientists who worked for more than 2 years to produce this report. It is an important source of data on EDCs and should be mandatory reading for everyone who is interested in protecting and improving human health.

Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.

Extracellular vesicles (EVs) including exosomes, microvesicles (MVs), and apoptotic bodies, are small membrane vesicular structures that are released during cell activation, senescence, or programmed cell death, including apoptosis, necroptosis, and pyroptosis. EVs serve as novel mediators for long-distance cell-to-cell communications and can transfer various bioactive molecules, such as encapsulated cytokines and genetic information from their parental cells to distant target cells. In the context of obesity, adipocyte-derived EVs are implicated in metabolic homeostasis serving as novel adipokines. In particular, EVs released from brown adipose tissue or adipose-derived stem cells may help control the remolding of white adipose tissue towards browning and maintaining metabolic homeostasis. Interestingly, EVs may even serve as mediators for the transmission of metabolic dysfunction across generations. Also, EVs have been recognized as novel modulators in various metabolic disorders, including insulin resistance, diabetes mellitus, and non-alcoholic fatty liver disease. In this review, we summarize the latest progress from basic and translational studies regarding the novel effects of EVs on metabolic diseases. We also discuss EV-mediated cross-talk between adipose tissue and other organs/tissues that are relevant to obesity and metabolic diseases, as well as the relevant mechanisms, providing insight into the development of new therapeutic strategies in obesity and metabolic diseases.

EDCs: negotiating the precautionary principle

Tobacco smoking is a leading concern to a global health; kills almost six million individuals annually and associated with life-threating health issues. Nearly 80% smokers live in middle- and low-income countries where illness and mortality rate due to cigarette smoking are higher. Tobacco smoking is interlinked with a numerous disease, comprising lungs cancer, chronic obstructive pulmonary disease, infertility, cardiovascular events, stroke, and metabolic disorders. Tobacco smoking has ability to obstruct and/or interfere in the function of endocrine system; has been entitled as endocrine disrupting chemicals (EDCs). EDCs are a heterogeneous group of exogenous compounds that can restrict with several facets of endogenous hormones. Standard role of endocrine system is reliant on hormonal/enzymatic pathway which may act as chemical and biological messengers to regulate the physiological functions of an organism. Tobacco smoking is also responsible to impair the regular metabolic pathway through interaction with members of superfamily of nuclear receptor such as peroxisome proliferator activated receptor, thyroid hormone receptors, liver X receptor, and retinoid X receptor. Smoking can also affect the multiple pathways including inflammatory response, DNA damaging, and oxidative stress. Reactive oxygen species (ROS) work as a second messenger in miscellaneous mitochondrial and cellular procedures and signaling pathways. On the other hand, excessive ROS might react with nucleic acid, lipids, carbohydrates, and protein causing inflammation and oxidative stress that are the main causes for the development of various metabolic disorders. Hence, this chapter will include the detailed discussion about the impact of cigarette smoking on metabolic disorder along with its effects on several enzymatic and metabolic pathways.KeywordsCigaretteEndocrine disrupting chemicalsMetabolic disordersCardiovascular diseases

BackgroundThere are conflicting results for relationships between serum vitamin D levels and metabolic diseases. The aim of this study was to investigate whether serum vitamin D levels were associated with various metabolic diseases including insulin resistance (IR), metabolic syndrome (MS), fatty liver (FL), and coronary artery calcification (CAC), along with assessing gender differences for these relationships in Korean adults.MethodsA total of 180,918 subjects (98,412 men and 82,506 women) who participated in a comprehensive health examination in the 2012–2013 period at Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University were included. Serum vitamin D and metabolic markers were analyzed and CAC was estimated. Subjects were divided according to quartile groups of serum vitamin D. To examine the relationships of serum vitamin D to metabolic diseases and metabolic factors, multivariate logistic analysis was conducted.ResultsHigh levels of serum vitamin D was associated with lower ORs for MS, IR and FL both in men and women (all p < 0.05). For men, ORs for CAC were significantly higher in third and the highest quartile groups for serum vitamin D in all the analyzed models (all p < 0.05). However, women showed no significant results between serum vitamin D and CAC.ConclusionsHigh levels of serum vitamin D were associated with lower risk of MS, IR and FL in both Korean men and women, but were associated with higher risk of CAC only in men, and not in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0432-3) contains supplementary material, which is available to authorized users.

The endocrine system consisting of hormone producing endocrine glands and their receptors; do control, coordinate, and regulate a variety of crucial physiological functions in human body. The hormones, the chemical messengers which are secreted directly into circulatory system regulate body’s growth and development, embryonic development, and primary sex characters, etc. The endocrine system manages to regulate glucose and lipid metabolism. However, it has been observed that a number of exogenous chemicals could interfere with the normal functioning of the endocrine system; disrupt the hormonal-synthesis and secretions, their transportation process and binding properties, and finally their physiological actions. Thus, they are termed as endocrine disrupting chemicals (EDCs). Unfortunately, such EDCs are ubiquitous in nature and move passively into human body through various unavoidable routes. They include but not limited to environmental toxicants, pesticides, herbicides, and pharmaceuticals. These EDCs impair the normal functions of hormones and the adverse effects are observed in the form of neurological disorders, sexual abnormalities in both genders, psychological and behavioral issues. They also cause metabolic disorders leading to obesity and type 2 diabetes. This chapter focuses on pharmaceutical products as EDCs and their role on incidence of insulin resistance and obesity. The pharmaceutical products could act as EDCs when they get discharged directly from pharmaceutical industries into environment through untreated wastewater. So, they could act as EDCs when they end up in normal human body through various routes and means. Secondly, the pharmaceutical products act as EDCs when they are used as medications for treatment of diseases but they show some undesirable off-target interaction with the endocrine system.

EDITORIAL article Front. Endocrinol., 31 August 2023Sec. Cardiovascular Endocrinology Volume 14 - 2023 | https://doi.org/10.3389/fendo.2023.1271565

<h3>Background</h3> Polycystic ovarian syndrome (PCOS) is the most common hormone disorder in females, affecting 4–20% of the population. PCOS is associated with metabolic dysfunction, pro-inflammation and mood disorders. Despite this, it is poorly understood, and diagnosis and management remain challenging in adolescents. Proteomics enables a better understanding of disease mechanisms and facilitates the identification of novel biomarkers. <h3>Aims</h3> 1. To better understand the clinical phenotype of PCOS in adolescents. 2. To undertake discovery proteomic urine profiling using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) to identify novel non-invasive biomarkers of PCOS. <h3>Method</h3> In this prospective longitudinal study, females aged 12–19 years meeting NIH diagnostic criteria for PCOS were recruited from adolescent endocrine and gynaecology clinics. At baseline and annual follow-up, the following were measured: pituitary, adrenal and ovarian hormones, anti-Müllerian hormone, inflammatory and metabolic markers including an oral glucose tolerance test, psychometric questionnaires, menstrual records, pubertal assessment, anthropometric parameters and pelvic ultrasounds. We have undertaken UPLC-MS/MS and developed new methods for discovery proteomic profiling of urine samples in an attempt to identify new disease mechanisms, drug targets and potential biomarkers. <h3>Results</h3> To date, 37 participants have been recruited (median age 15.0 years, range 12.6–18.3), and 22 have completed annual follow-up. Clinical signs at presentation included acne (89%), hirsutism (78%), acanthosis nigricans (49%) and overweight/obesity (81%). Two-thirds of participants had depressive or anxiety symptoms. Only one-third were known to mental health services. Metabolic dysfunction was common; elevated body fat (88%), dyslipidaemia (24%), insulin resistance (62%), and impaired fasting glucose, impaired glucose tolerance or type 2 diabetes (40%). AMH was elevated in one-third of participants and three-quarters had an elevated free androgen index. Elevated inflammatory markers (CRP/ESR) were present in 40% participants. Only three participants had definitive ultrasonographic evidence of PCOS. Interventions included lifestyle advice only (27%), combined oral contraceptive pill (COCP) ± anti-androgen (16%), metformin (30%) or metformin + COCP ± anti-androgen (27%). <h3>Conclusion and Future Directions</h3> Diagnosing PCOS in adolescents remains challenging; acne and irregular menstrual cycles are common and ultrasonographic diagnosis of PCOS is suboptimal. Given the high prevalence of metabolic and mental health disorders, early diagnosis and intervention are imperative. We describe the use of urinary proteomics to study metabolic pathways affected in PCOS and the potential identification of novel non-invasive biomarkers. Subsequently, we will use this hypothesis-generating data-set to create a non-invasive and clinically translatable assay to aid diagnosis and stratify management of this common adolescent condition.

Estrogen receptors are some of the primary targets of endocrine-disrupting chemicals (EDCs). In a new report in this issue of EHP, biochemical, structural, biophysical, and cell-based experiments reveal critical information about the activity of 12 EDCs at the molecular and atomic levels.1 The EDCs tested, including the plasticizer bisphenol A and the flame retardant tetrachlorobisphenol A, are suspected to have a role in the development of various cancers and developmental, reproductive, and metabolic disorders via interactions with estrogen receptors. A new study provides the visualization, at atomic resolution, of the estrogen receptor bound to various endocrine-disrupting chemicals. The insights gained may help guide the development of safer chemicals. “A better understanding of the many ways by which environmental pollutants interfere with nuclear receptor signaling will help in predicting the residual hormonal activity of an existing industrial compound and rationalizing the development of new analogues devoid of nuclear receptor activities,” says study coauthor William Bourguet, team leader at the Center for Structural Biochemistry, Montpellier University, France. EDCs can undermine the endocrine system by either mimicking or blocking (antagonizing) endogenous hormones, or by interfering with their synthesis, metabolism, or transport.2,3 Estrogen receptors, which occur as ERα and ERβ subtypes, have been particularly well studied with regard to EDCs.4,5 The predominant subtype of estrogen receptor varies by tissue throughout the body, although the two are sometimes co-expressed. The ligand that normally interacts with these receptors is 17β-estradiol, which is critical to the growth and development of tissues throughout the body. Interference with the action of 17β-estradiol has been associated with cancer, infertility, obesity, and diabetes.6,7 Predicting the potential outcomes of EDC exposure is complicated by the fact that numerous unrelated chemicals can bind to ERα and/or ERβ.1,8 “Because the chemical structures of environmental compounds are generally very different from those of natural compounds, their binding modes are difficult to predict,” says Bourguet. In the current study, the researchers parsed estrogen receptor activity based on a detailed examination of functional domains characteristic of both receptor subtypes: the N-terminal domain, which includes activation function 1 (AF-1), and the C-terminal ligand-binding domain, which contains AF-2. AF-2 activity depends on a ligand being bound, but AF-1 activity is independent of the ligand. AF-1 integrates signals from AF-2 and other pathways to modulate the receptor’s ultimate activity—gene transcription. “Although not directly linked, the two activation functions can work synergistically or independently depending on the nature of the bound ligand,” says Bourguet. “One of our aims was to evaluate the role of each function in both receptor subtypes and in the presence of the different compounds,” he says. To this end, the researchers first generated HeLa cells containing a reporter gene paired with wild-type ERα or ERβ or with mutant receptors lacking AF-1. Subsequent assays revealed which of the 12 EDCs could activate each subtype as well as how critical AF-1 was to the activation process. All the EDCs could bind to the receptors; however, some activated ERα and ERβ equally, while others activated only one or the other. The presence of AF-1 modulated the activity, particularly for ERβ, whereas AF-2 was more important for ERα activation. Competitive assays demonstrated the EDCs’ binding affinities relative to 17β-estradiol, which ranged from very similar to 50,000-fold lower values. Next, protein crystallization experiments demonstrated each chemical’s fit in the ligand-binding pocket of ERα. These structural data reflected the findings from the in vitro assays and helped explain the compounds’ differential activity on ERα and ERβ.1 The precise response of an estrogen receptor to a specific ligand hinges on the cellular context and the presence of cofactors,9 and it’s still unknown whether in vitro observations reflect what happens in vivo. “This is a critical aspect to understanding how estrogenic chemicals really behave in tissues, and why this study is important,” says Yukitomo Arao, staff scientist in the NIEHS Reproductive and Developmental Biology Laboratory. “In general, it is important to understand the differential tissue functionality of various estrogenic compounds; more narrowly, for example, AF-1 activity is regulated by the gene promoter context and is cell-type specific,” says Arao, who was not involved in the study. A potential weakness of this study is the use of a constitutive active mutant of ERα to facilitate crystallography, which Arao suggests might alter the chemical–receptor interactions. Another potential weakness is the exclusive use of HeLa cells; AF-1 varies between cell types and tissues, so its behavior in one cell line may not reflect how it will act in another. “However, the authors mentioned the differential estrogenic activity of compounds in different cells in their discussion,” Arao says, “and I hope they will make similar stable cell lines using different cell types to reevaluate EDCs’ estrogenic activities.”