Endocrine-disrupting chemicals and PCOS: A novel contributor in the etiology of the syndrome

Defining an endocrine disruptor

Over half a century has passed since the first observation that environmental pollution can potentially represent a big threat to public health. Specifically, in 1962, Rachel Carson underlined the adverse effects of pesticides (dichlorodiphenyltrichloroethane -DDT) on sexual development and reproduction, postulating that “as the tide of chemicals born of the Industrial Age has arisen to engulf our environment, a drastic change has come about in the nature of the most serious public health problems” . The “diethylstilbestrol (DES) catastrophe” followed almost a decade later, in which prenatal use of diethylstilbestrol (DES), an estrogen-based drug that was thought to prevent miscarriage, was linked with vaginal adenocarcinoma in a series of patients, establishing the concept of “hormone disruption” as an etiologic parameter for human health perturbations .

However, it was in 1991, when a diverse group of 21 experts assembled at the Wingspread Conference Center in Racine, Wisconsin, USA (July 26–28, 1991) and introduced for the first time in the scientific community the terms “endocrine disruption” and “endocrine disruptor”, opening up a pivotal chapter in the field of contemporary Environmental Endocrinology . As years came by, mounting evidence was accumulating regarding EDCs’ effects on multiple endocrine systems, including thyroid, reproduction, neurodevelopment, obesity, and metabolism. In particular, the coinciding rapid increase in the incidence of various endocrine diseases (obesity, diabetes mellitus, thyroid disorders) during the past decades has strengthened the belief that EDCs are their potential environmental drivers.

EDCs are now recognized as one of the most severe threats to public health, potentially emerging as one of the leading environmental risks globally . Subsequently, various scientific societies, non-governmental organizations, and governmental agencies, such as the Endocrine Society , the International Federation of Gynecology and Obstetrics , World Health Organization (WHO), the United Nations Environment Programme (UNEP), and the American Academy of Pediatrics are acknowledging the role of EDCs and issuing extensive reports concerning their adverse effects in the human body.

According to them, EDCs are defined as exogenous chemicals or mixtures of chemicals that interfere with any aspect of endogenous hormonal signaling, affecting production, release, transport, cellular metabolism, binding action, and elimination of hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process. They represent a continuously expanding, highly heterogenous group of natural or man-made chemical compounds, originating from various, commonly encountered in everyday life sources, such as industrial solvents, plastics, plasticizers, storage containers, pesticides and fungicides, pharmaceutical agents, highly processed foods, cigarettes smoking, textiles and personal care products ( Fig. 1 ).

Simultaneously, while the scientific community was broadening its knowledge regarding EDCs, over the last several years, a series of economic evaluations estimated the financial impact of EDCs in the frail healthcare system . Specifically, in a paper by Trasande et al., the total annual cost of all medical conditions probably attributable to EDCs in the European area was estimated to be 191 billion Euros , while when focusing on diabetes and obesity, attributed to EDC exposure associated costs were calculated to be over €18 billion per year . Although the aforementioned disease burden costs are considered by a share of scientists as highly speculative and an arbitrary estimation of the financial impact of EDCs , there is no doubt that EDCs burden global healthcare systems via their detrimental health consequences.

All the above have urged governments globally to restructure their regulations and policies regarding chemical substances and their environmental hazard, not only to improve citizens’ health via reduction or elimination of exposures—but also restrict the associated financial burden. In this context, recently European Commission has embraced a new strategic approach, based on the precautionary principle, aiming at the minimization of overall exposure to EDCs and the development of a thorough research basis for effective decision-making, via promoting dialogue and allowing all stakeholders to be heard . Although this is a positive step, regulatory bodies still have to put a lot of effort towards decreasing human exposure to EDCs and establishing global policies.

The fundamentals of endocrine disruptors’ mechanisms of action

Until today, endocrine disrupting properties have been recognized in over 1000 natural or man-made chemical compounds. Naturally occurring EDCs can be found in plants and can be introduced into the food chain through consumption by animals/humans (such as phytoestrogens). Synthetic EDCs have been widely utilized as drugs [diethylstilbestrol (DES)], pesticides [dichlorodiphenyltrichloroethane (DDT)], plastics [Bisphenol A (BPA)], plasticizers/dispersants [phthalates], or industrial solvents [polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs)]. As the list of EDCs is continuously growing and their uses are expanding, the human body is becoming the recipient of a variety of environmental contaminants, via multiple routes, including air, water, food, and everyday consumer products. Subsequently, EDCs have been detected in various biological fluids in humans, such as sera, urine, amniotic fluid, and breast milk.

Although the concept of endocrine disruption is currently considered strong and validated, the underlying mechanisms whereby EDCs can induce their adverse effects in humans or the environment are only partially understood and remain a challenging scientific enigma. However, multidisciplinary research in endocrinology, ecotoxicology, toxicology, epidemiology, clinical research, epigenetics, and environmental sciences have established the fundamentals of their mode of action. In a recent consensus of an international group of experts, an effort was made to recognize the key characteristics of EDCs and reflect on how these can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs. Apart from identifying their intrinsic endocrine-disrupting hazard, this approach can serve as a universal framework not only for the scientific community but also for jurisdictions and regulatory agencies .

Following the principles of endocrine physiology, EDCs can exert their disrupting effects multifariously. More specifically, EDCs can directly perturb signaling pathways regulating steroid biosynthesis and/or metabolism of the human body, by interacting with, activating, or antagonizing nuclear and transmembrane hormone receptors, as well as via altering hormone receptor expression and signal transduction (including changes in protein or RNA expression, post-translational modifications and/or ion flux) in hormone-responsive cells. Simultaneously, EDCs can modulate hormone synthesis, hormone distribution or circulating hormone levels, hormone metabolism/clearance, or the fate of hormone-producing or hormone-responsive cells . Among their cellular effects, literature has shown that EDCs can also target mitochondria, perturbing mitochondrial bioenergetics, biogenesis, and dynamics and promoting excessive ROS production and activation of the mitochondrial pathway of apoptosis. This mitochondrial dysfunction, except for being particularly crucial for insulin-responsive tissues and metabolic homeostasis, is also emerging as a contributing factor in the pathogenesis of PCOS . Finally, apart from all the above modes of action, another major mechanism in which EDCs interfere with hormone action is by inducing epigenetic changes, especially during development and differentiation, by modifying epigenetic processes, such as DNA and histone modifications and non-coding RNA expression .

All the above features should not be used as a “checklist.” The innate disrupting hazard of an EDC is not necessarily increasing when more than one from the above-mentioned mechanisms is observed. Even one pathogenetic mechanism can be sufficient to disrupt an entire system, as long as it targets/interferes with a key event in hormone action/signaling. For example, BPA and DES are two EDCs exerting their effects via multiple ways, such as interacting or antagonizing with different receptors, altering signal transduction in various pathways, or inducing epigenetic changes. On the other hand, perchlorate, an inorganic ion that is widely manufactured for use in rocket propellant, matches, fireworks, and other explosives, inhibits thyroid hormone synthesis only by acting as a potent competitive inhibitor of iodide uptake through the sodium–iodide symporter from humans, rodents and other vertebrates .

Finally, it should be mentioned that EDCs can be potent even at very low doses and a long latency period between exposure and disease can be observed. Some of them have low accumulation in the human body (BPA, phthalates), while others are very lipophilic, accumulating easily in the food chain and the adipose tissue (persistent organic pollutants - POPs). Furthermore, they are usually characterized by a much lower affinity for hormone receptors, compared to natural ligands, as well as low-dose effects and non-monotonic dose- responses, which means that they can promote disrupting effects even in very low levels of exposure . Added to all the above particularities, EDCs are being added on top of the endogenous hormonal milieu, such that complex mixtures, dose additivity, and synergism between and among hormones and chemicals are the norms, further complicating their understanding .