Review
Endocrine disrupting chemicals and disease susceptibility

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Abstract

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products – including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.

Highlights

► Chemical exposures during development can alter disease susceptibility later in life. ► Endocrine disrupting chemicals (EDCs) can produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. ► EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones.

Introduction

EDs are synthetic chemicals that were originally designed for a specific action such as a pesticide, plasticizer, or solvent, but now have been found to have a side effect that when absorbed into the body causes them to either mimic or block hormones and disrupt the body's normal functions. This disruption can occur by altering normal hormone levels, inhibiting or stimulating the production and metabolism of hormones, or changing the way hormones travel through the body, thus affecting the functions that these hormones control. EDCs were originally thought to exert their actions solely through nuclear hormone receptors, including estrogen receptors (ERs), androgen receptors (ARs), progesterone receptors, thyroid receptors (TRs), and retinoid receptors, among others (Table 1) [1]. However, recent evidence shows that the mechanisms by which EDCs act are much broader than originally recognized. Indeed, studies have shown that in addition to altering nuclear receptor signaling, EDCs are capable of acting through nonsteroid receptors, transcriptional coactivators, enzymatic pathways involved in steroid biosynthesis and/or metabolism, and numerous other mechanisms that converge upon endocrine and reproductive systems [1], [2]. Other less well known mechanisms of action of EDCs include direct effects on genes [3] and their epigenetic impact [4]. These effects are particularly troubling since alterations in genetic programming during early stages of development may have profound effects years later and may also lead to transgenerational inheritance of disease (Fig. 1) [5].

There are several characteristics of the endocrine system that must be understood in order to develop a full understanding of the mechanisms of actions and the consequences of exposure to EDCs. For instance, similar to hormones, EDCs can function at very low doses in a tissue specific manner. EDCs may also exert non-traditional dose–responses due to the complicated dynamics of hormone receptor occupancy and saturation. Thus low doses may have more impact on a target tissue than higher doses, and the effects and dose–response curve may be entirely different. The age at which an individual is exposed to an EDC also has important implications on resulting health consequences. Indeed, it is now clear that exposure to EDCs during development results in different effects than exposures during adulthood. Adults require higher concentrations for EDCs to cause toxicity and their effects only last as long as the EDC is present. Low dose exposure during development can result in disruptions that lasts long after the EDC is gone from the body. For this reason, the field of endocrine disruption coined the term “the fetal basis of adult disease”, or FeBAD, to describe the interactions between the developing organism and the environment that determine the propensity of that individual to develop disease later in life [1]. This concept has been extended beyond the fetal period to include the early postnatal developmental period when organs continue to undergo substantial development. DOHaD (developmental origins of health and disease) describes the interactions between the developing organism and the environment that determine the propensity of that individual to develop disease across its lifespan [1].

Evidence in animal models suggests that EDCs may affect not only the exposed individual but also the offspring and subsequent generations. The mechanism of transmission involves non-genomic modifications of the germ line such as changes in DNA methylation and histone acetylation. Altogether, EDCs pose a significant challenge to our industrialized society and to the health of humans and the environment. Indeed, due to their wide commercial use and direct link to adverse human health outcomes, the Endocrine Society published a scientific statement in 2009 indicating that endocrine disruptors pose a “significant concern for public health” [1].

Section snippets

Nuclear receptor signaling

EDCs are structurally similar to many hormones, function at extremely low concentrations, and many have lipophilic properties. EDCs are capable of mimicking natural hormones and maintain similar modes of action, transport, and storage within tissues. The properties of these chemicals, while unintended, make them particularly well suited for activating or antagonizing nuclear hormone receptors. Thus, there is virtually no endocrine system immune to these substances, because of the shared

Male reproduction and development

Given the fact that both hormone production and action are regulated in large part by the reproductive tissue, it is not surprising that EDCs contribute to many adverse reproductive health outcomes in developing and adult humans. Epidemiological data has revealed an increase in male reproductive function disorders over the past 50 years, suggesting a correlative relationship with the increasing amounts of EDCs in the environment [64]. In the context of male reproductive health, EDCs have been

Conclusion

Humans are exposed to thousands of chemicals during their lifetime, through the air, food, and water. A significant number of these chemicals can be toxic since they can disrupt the endocrine system. Over the past decade, the list of chemicals with endocrine disrupting activity has dramatically increased [123]. Evidence has shown that EDCs compromise the reproductive system, thyroid signaling mechanisms, as well as tissues and organs associated with energy metabolism, glucose control, fat cell

Statement

This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government.

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