Environmental endocrine disruptors and obesity

Obesity has recently become an epidemic. The rise in the childhood obesity incidence is of particular concern. High density caloric diets and physical inactivity are the main causes of obesity. Besides that, is generally accepted that obesity has a genetic predisposition, unchanged for the past few decades. The environment via endocrine disruptors might be, at least partly responsible for the globally obesity epidemic. Endocrine disruptors are environmental chemical compounds produced by human activity that either mimic or block hormonal actions. Many of them modulate lipid metabolism and adipogenesis, contributing to obesity initiation and/or exacerbation. Here we provide an overview of the role of the environmental chemical obesogens and their impact on obesity. Keywords: obesity, endocrine disruptors, epigenetics.     

环境内分泌干扰物与儿童性早熟发病的关系

环境内分泌干扰物是普遍存在于环境中的一类化学物质,能够造成机体内分泌系统功能紊乱.环境内分泌干扰物易被机体吸收而不易排出,相互之间具有协同作用,且具有遗传性及传代性,因此能严重影响人类的健康.环境内分泌干扰物可以导致下丘脑-垂体-性腺轴形态和功能的改变,影响其调节功能;干扰雌激素的代谢及转运,提高体内雌激素水平;激活雌...     

HIV and hormones

The term "hormone" broadly refers to any type of chemical messenger, but is most often used to denote chemicals produced by the endocrine glands. Hormones play a key role in maintaining homeostasis (a steady state of equilibrium) and regulating many bodily processes--everything from growth and metabolism to sexual function and reproduction. Over- or underproduction of endocrine hormones can contribute to a wide variety of medical conditions. Diseases such as HIV that affect the whole body can interfere with proper endocrine function, and hormones, in turn, can affect HIV disease progression.     

Pathogenesis of occupational asthma.

The development of occupational asthma (OA) is likely to result from the complex interaction of environmental and host factors. This article addresses a series of issues relating to the multiple environmental factors that could affect the initiation of OA, including the intrinsic characteristics of causative agents, as well as the influence of the level, mode and route of exposure. Although the clinical and pathological features of OA caused by low molecular weight agents resemble those of immunoglobulin (Ig)E-mediated asthma, the failure to detect specific IgE antibodies against most of these agents and/or poor association with disease status have resulted in intense speculation about alternative or complementary physiopathological mechanisms leading to airway sensitisation. In this contribution, the roles of specific immunoglobulin E and G antibodies, cell-mediated immunity and inflammatory effector cells are critically reviewed. Recent advances in the characterisation of the molecular interactions between chemical sensitisers and human airway proteins provide promising avenues for elucidating the immunological basis of occupational asthma caused by low molecular weight agents.     

Ovarian intrafollicular processes as a target for cigarette smoke components and selected environmental reproductive disruptors

Steroidogenesis, expansion of oocyte-cumulus complex, and meiotic maturation of the oocyte represent intrafollicular processes taking important part in the background of successful fertilisation. The reproductive health of female could be affected by a number of endogenous as well as exogenous factors, such as exposure to agents from specific lifestyle habits, environmental pollutants with endocrine disrupting properties, or heavy metals. Published data indicate that exposure to chemicals may cause alterations in reproductive behavior and contribute to sub-fecundity, infertility, or ovarian failure. Female reproductive functions can be compromised by exposure to toxic chemicals at a variety of sites, including ovary or reproductive tract. Substantial harmful effects of cigarette smoke on fecundity and reproduction have become apparent but are not generally appreciated. The effects of cigarette smoke components (cadmium, nicotine, cotinine) absorbed into the organism on intrafollicular processes may thus in part explain the negative impact of smoking on female fertility. Moreover, it is now evident that a variety of man-made pollutants present in the environment are capable to disrupt normal endocrine function in many species. Examples of these "endocrine disrupters" include plasticizers, such as phthalates and bisphenol A. The effects of selected environmental chemicals on the processes of steroidogenesis, expansion of oocyte-cumulus complex, and meiotic maturation of the oocyte are summarized in the present paper and possible mechanisms of action of these agents are suggested. However, for complete understanding the mechanisms by which chemical agents from the environment can affect the intrafollicular processes, a lot of further investigation is needed.     

Endocrine effects of Fukushima: Radiation-induced endocrinopathy

The unfortunate accidents of Chernobyl and Fukushima have led to an enormous amount of radioactive material being released into the atmosphere. Radiation exposure to the human body may be as a result of accidents, such as those in Chernobyl and Fukushima, or due to occupational hazards, such as in the employees of nuclear plants, or due to therapeutic or diagnostic procedures. These different sources of radiations may affect the human body as a whole or may cause localized damage to a certain area of the body, depending upon the extent and dosage of the irradiation. More or less every organ is affected by radiation exposure. Some require a higher dose to be affected while others may be affected at a lower dose. All the endocrine glands are susceptible to damage by radiation exposure; however, pituitary, thyroid and gonads are most likely to be affected. In addition to the endocrine effects, the rates of birth defects and carcinomas may also be increased in the population exposed to excessive radiation.     

Perturbateurs endocriniens : échos des congrès d’Endocrinologie 2012

The increased prevalence of certain diseases, along with the development of new technologies and industrialization raised the possibility of the involvement of environmental factors, industrial products, nutritional factors, infections, drugs… and endocrine disruptors. These factors may interfere via signaling pathways specific to the organism. Endocrine Disrupting Chemicals (EDCs) have been redefined by the Endocrine Society in 2012 as “exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action”. They have therefore potentially deleterious effects on development, growth, metabolism, reproduction, the nervous, immune and cardiovascular systems. Therefore, they constitute a real public health issue. Their long half-life may explain delayed effects and their often lipophilic character may promote maternofetal transmission. Exept diethylstilbestrol (DES), few formal proofs have been made on the direct role of EDCs ; arguments are based on cross-sectional studies, in vitro models and animal models. Basic research puts insight into mechanisms of action of EDCs but many questions remain unanswered. Epidemiological data are difficult to interpret because of interindividual differences in susceptibility to EDCs and of nonlinear/nonmonotonique action (as opposed to toxic dose effect), multiple interactions between environmental agents (additive effects and/or synergistic and/or antagonists), the role of the window of exposure, latency, and the possibility of transgenerational effects.     

Fetal and neonatal endocrine disruptors

Endocrine disruptors are substances commonly encountered in every setting and condition in the modern world. It is virtually impossible to avoid the contact with these chemical compounds in our daily life. Molecules defined as endocrine disruptors constitute an extremely heterogeneous group and include synthetic chemicals used as industrial solvents/lubricants and their by-products. Natural chemicals found in human and animal food (phytoestrogens) also act as endocrine disruptors. Different from adults, children are not exposed only to chemical toxins in the environment but may also be exposed during their intrauterine life. Hundreds of toxic substances, which include neuro-immune and endocrine toxic chemical components that may influence the critical steps of hormonal, neurological and immunological development, may affect the fetus via the placental cord and these substances may be excreted in the meconium. Children and especially newborns are more sensitive to environmental toxins compared to adults. Metabolic pathways are immature, especially in the first months of life. The ability of the newborn to metabolize, detoxify and eliminate many toxins is different from that of the adults. Although exposures occur during fetal or neonatal period, their effects may sometimes be observed in later years. Further studies are needed to clarify the effects of these substances on the endocrine system and to provide evidence for preventive measures.     

Lipid Effects of Endocrine Medications

Various alterations of lipid homeostasis have a significant role in the pathophysiology of the artherosclerotic process. The effects of usual lipid-lowering agents such as statins, fibrates, or niacin are well known, but other endocrine therapeutic agents could also affect the blood levels of various lipoproteins and, in turn, influence atheroma formation. In this review, we attempt to summarize the effect of several hormonal and non-hormonal endocrine agents on lipid metabolism, including insulin, thyroid hormone, sex hormones, glucocorticoids, growth hormone, and several anti-diabetic agents.     

Environmental epigenetics: a role in endocrine disease?

Endocrine disrupting chemicals that are structurally similar to steroid or amine hormones have the potential to mimic endocrine endpoints at the receptor level. However, more recently, epigenetic-induced alteration in gene expression has emerged as an alternative way in which environmental compounds may exert endocrine effects. We review concepts related to environmental epigenetics and relevance for endocrinology through three broad examples: 1) effect of early-life nutritional exposures on future obesity and insulin resistance, 2) effect of lifetime environmental exposures such as ionizing radiation on endocrine cancer risk, and 3) potential for compounds previously classified as endocrine disrupting to additionally or alternatively exert effects through epigenetic mechanisms. The field of environmental epigenetics is still nascent, and additional studies are needed to confirm and reinforce data derived from animal models and preliminary human studies. Current evidence suggests that environmental exposures may significantly impact expression of endocrine-related genes and thereby affect clinical endocrine outcomes.     

Effects of Feeding on Bone Metabolism

Bone metabolism responds to long-term energy balance, but is also regulated acutely by feeding. In vitro, animal and human studies have demonstrated complex effects of feeding on bone metabolism, which may be mediated through multiple interacting pathways. The most important mediators of the effects of feeding on bone metabolism are likely to be enteric and pancreatic hormones, such as incretins, amylin, preptin, pancreatic polypeptide, and peptide YY. These mediators may regulate bone turnover by direct effects on bone cells and through central nervous system pathways. Small human studies have been conducted to assess the therapeutic potential of these mediators, and although not all had significant effects, this is promising field for new treatments. Dietary composition may also influence bone metabolism, for example protein intake may exert effects through IGF-1, and acid-base balance may influence osteoclast activity and renal calcium excretion. In conclusion, bone metabolism is regulated by long-term energy balance, acute effects of feeding and dietary composition, and there are likely to be multiple interactions between these processes. Some of the endocrine mediators of feeding and bone metabolism have potential as therapeutic agents.     

Spirometry and tests of bronchial hyperresponsiveness in population studies.

The use of spirometry in epidemiological studies has provided objective evidence of the acute and chronic effects of occupational and environmental exposure to many agents as well as data on exposure-response relationships necessary for establishing control levels. Methacholine or histamine challenge testing for the measurement of non-specific bronchial hyperresponsiveness (NSBH) in epidemiological settings is safe when carried out according to a standardised protocol. Measurement of NSBH, a useful tool in the clinical assessment of occupational asthma, has also been used in screening workers in surveys of workforces at risk for occupational asthma. Standardisation and quality control are the key to the success of using lung function testing in the field.     

Inhibition of estrogen actions in human gynecological malignancies: New aspects of endocrine therapy for endometrial cancer and ovarian cancer

Endometrial carcinoma and possibly ovarian carcinoma are considered “estrogen-dependent tumors” in human gynecological malignancies. In endometrial carcinoma, the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are different from those in human breast carcinoma, although both of them are considered “estrogen-dependent malignancies”. Specific and effective endocrine treatment of endometrial carcinoma should be explored, although progestin agents have been widely used for a long time. Aromatase inhibitors, the most effective endocrine agents of breast carcinoma, retinoids, metabolites of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) gamma ligands, used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates for possible endocrine treatment of endometrial carcinoma.     

The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development

Αbstract The delivery of the appropriate thyroid hormones quantity to target tissues in euthyroidism is the result of unopposed synthesis, transport, metabolism, and excretion of these hormones. Thyroid hormones homeostasis depends on the maintenance of the circulating ‘free’ thyroid hormone reserves and on the development of a dynamic balance between the ‘free’ hormones reserves and those of the ‘bound’ hormones with the transport proteins. Disturbance of this hormone system, which is in constant interaction with other hormone systems, leads to an adaptational counter-response targeting to re-establish a new homeostatic equilibrium. An excessive disturbance is likely to result, however, in hypo- or hyper- thyroid clinical states. Endocrine disruptors are chemical substances forming part of ‘natural’ contaminating agents found in most ecosystems. There is abundant evidence that several key components of the thyroid hormones homeostasis are susceptible to the action of endocrine disruptors. These chemicals include some chlorinated organic compounds, polycyclic aromatic hydrocarbons, herbicides, and pharmaceutical agents. Intrauterine exposure to endocrine disruptors that either mimic or antagonize thyroid hormones can produce permanent developmental disorders in the structure and functioning of the brain, leading to behavioral changes. Steroid receptors are important determinants of the consequences of endocrine disruptors. Their interaction with thyroid hormones complicates the effect of endocrine disruptors. The aim of this review is to present the effect of endocrine disruptors on thyroid hormones physiology and their potential impact on intrauterine development.     

Endocrine manifestations of human immunodeficiency virus (HIV) infection

Endocrine manifestations of HIV infection include both pathological changes and disturbances in function. Mechanisms include direct infection of glands by HIV or opportunistic organisms, infiltration by neoplasms, side effects of drugs, and production of humoral factors that may alter metabolism. The adrenal gland is most often affected, but virtually every endocrine system may be involved. Dysfunction is often subtle, with symptoms overlapping those of the HIV infection itself. Endocrine manifestations may be found at any time in the course of the disease, from the asymptomatic HIV-positive stage through full-blown AIDS. Optimal management of these patients may include a careful search for, and appropriate treatment of, associated endocrine abnormalities.     

Immunohistochemical localization of interleukin-6 in peripheral human endocrine glands

Interleukin-6 (IL-6) is a pleiotropic cytokine with differentiation and growth-promoting effects. Extensive studies in experimental animals denote that IL-6 is produced in various endocrine organs and participates in the local control of endocrine cell function. The expression of this cytokine in human endocrine glands, however, has only been examined in a limited number of studies. We investigated the immunohistochemical expression and localization of IL-6 in a variety of peripheral human endocrine glands. In the adrenals, IL-6 immunoreactivity was detected in all three zones of the cortex. The reticularis and glomerulosa zones were more heavily stained as compared with the slight immunoreactivity of the fasciculata zone. In the adrenal medulla, chromaffin and sustentacular cells were variably positive. A substantial number of follicular thyroid cells were strongly immunoreactive for IL-6 in all normal and hyperplastic thyroids examined. Parafollicular cells were negative. Parathyroid chief cells were mildly positive; selective and more intense staining was observed in acidophilic cells. Pancreatic islet cells were variably positive. In the testis positive staining was selectively observed in both Leydig and Sertoli cells. In conclusion, IL-6 immunoreactivity is present in almost all the human endocrine glands and it expressed in a cell-specific manner. These observations provide further support for the existence of local immune-endocrine interactions.     

Endocrine disruption in the human fetal testis: use of a xenograft system to assess effects of exposure to environmental agents and pharmaceutical drugs

BackgroundMany environmental chemicals have been proposed as endocrine disruptors in the fetal testis. Studies in rats have demonstrated reproductive abnormalities after in-utero exposure to environmental chemicals (eg, phthalates) or pharmaceutical drugs such as paracetamol. Whether such effects also occur in the human fetal testis has been difficult to determine. We have recently demonstrated that xenografting of human fetal testis tissue results in normal seminiferous cord formation and cellular development/function. We aimed to determine the effects of proposed endocrine disruptors (eg, phthalates, paracetamol) on the human fetal testis using a xenograft approach.MethodsHuman fetal testes (14–20 weeks’ gestation, n=17) obtained from elective terminations were xenografted into nude mice. Host mice received di-n-butyl phthalate (500 mg/kg/day), paracetamol (350 mg/kg/day), or vehicle during the grafting period. Testosterone production was determined by measurement of host animal seminal vesicle weight. Morphological and immunohistochemical analysis with a range of markers was performed to investigate seminiferous cord structure, steroidogenesis, and cellular development.FindingsExposure to paracetamol resulted in a significant reduction in seminal vesicle weight (mean 13·6 mg [SD 8·5] vs 10·0 [5·4], p<0·01). Expression of 3β hydroxysteroid dehydrogenase (3β-HSD) was also decreased in paracetamol compared with vehicle treated grafts. Exposure to di-n-butyl phthalate did not result in a reduction in testosterone or 3β-HSD expression in human xenografts (in contrast to rats); however, testosterone independent germ cell effects were demonstrated with a reduction in gonocytes in di-n-butyl phthalate exposed grafts compared with vehicle (mean 13% [SD 11·6] vs 23 [11·3], p<0·05).InterpretationThese results suggest that paracetamol may impair testosterone production in the human fetal testis, whereas phthalates do not. This highlights important differences between rat and man in terms of the effects of chemical exposure on the developing testis.FundingWellcome Trust and British Society for Paediatric Endocrinology and Diabetes.     

Amphibian metamorphosis as a model for studying endocrine disruption on vertebrate development: Effect of bisphenol A on thyroid hormone action

Thyroid hormone (TH) is essential for proper development in vertebrates. TH deficiency during gestation and early postnatal development produces severe neurological, skeletal, metabolism and growth abnormalities. It is therefore important to consider environmental chemicals that may interfere with TH signaling. Exposure to environmental contaminants that disrupt TH action may underlie the increasing incidence of human developmental disorders worldwide. One contaminant of concern is the xenoestrogen bisphenol A (BPA), a chemical widely used to manufacture polycarbonate plastics and epoxy resins. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. As TH action at the cellular level is highly conserved across vertebrate species, amphibian metamorphosis serves as an important TH-dependent in vivo vertebrate model for studying potential contributions of BPA toward human developmental disorders. Using Xenopus laevis as a model, we and others have demonstrated the inhibitory effects of BPA exposure on metamorphosis. Genome-wide gene expression analysis revealed that surprisingly, BPA primarily targets the TH-signaling pathway essential for metamorphosis in Xenopus laevis. Given the importance of the genomic effects of TH during metamorphosis and the conservation in its regulation in higher vertebrates, these observations suggest that the effect of BPA in human embryogenesis is through the inhibition of the TH pathway and warrants further investigation. Our findings further argue for the critical need to use in vivo animal models coupled with systematic molecular analysis to determine the developmental effects of endocrine disrupting compounds.     

Environmental Exposures and Hepatocellular Carcinoma

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC.     

Direct and indirect influences of a 14 days oestradiol-17 beta treatment on the endocrine pancreas of the female rat

The relationship between the hyperinsulinism induced by 14-days oestradiol treatment and the trophic action of this hormone on the endocrine pancreas was studied. The possible interference of the adrenal glands in these effects of oestradiol was investigated using comparisons between adrenalectomized and/or ovariectomized rats. Oestradiol increased the dry weight of the islets of Langerhans and enhanced total incorporation of [3H] leucine into newly synthetized proteins during a glucose stimulation independently of the presence of the adrenal glands. Conversely, the presence of the adrenal glands was necessary for the expression of the enhancing actions of oestradiol such as the production of insulin hypersecretion, increased insulin biosynthesis and a higher proportion of light granules inside the B cells. These results were in favour of a direct trophic role of oestradiol on the endocrine pancreas, but also of an indirect role of this hormone in the stimulation of the insulin secretion and biosynthesis, mediated by glucocorticoids.