ReviewEpigenetic effects of endocrine-disrupting chemicals on female reproduction: An ovarian perspective
Introduction
Female fertility disorders are becoming increasingly prevalent and an emerging women’s health concern [13], [63], [74]. These disease outcomes reflect the interplay between individuals’ genetic composition and the environment. Since the genetic composition at the population level is relatively slow to change, the significant role of our dramatically changed environment, in the last century, has to be considered. The impact of the environment, especially during development is highly relevant to adult health and is highlighted by the Barker hypothesis, also known as the developmental origins of health and disease (DoHAD) [11], [12], [105]. Although the Barker hypothesis was originally based on nutritional deprivation in utero and cardiovascular or metabolic disorders in adulthood, its perspective can be applied to developmental exposure to environmental endocrine-disrupting chemicals (EDCs) and fertility disorders in females during adulthood [74].
EDCs are synthetic and natural compounds in the environment that interfere with (i.e., mimic and/or antagonize) the actions of endogenous hormones and disrupt the functions of the endocrine system. The United States Environmental Protection Agency (EPA) has identified hundreds of EDCs that have estrogenic, anti-estrogenic, or anti-androgenic activities [13], [65], [322]. Potentially there are many compounds that either already exist in the environment or are newly introduced, whose effects have not yet been studied in the female reproductive system. EDCs include several groups of chemicals such as insecticides, herbicides and fungicides; plastics and plasticizers; surfactants; industrial chemicals such as polychloro biphenyls (PCBs), polybrominated biphenyls (PBBs), and dioxins; flame retardants; pharmaceuticals; and phytoestrogens such as genistein and coumestrol. There are numerous ways in which exposures to EDCs can occur. While a few compounds are for medicinal use, exposures to the vast majority of these EDCs are through unintended exposure. For example, DDT, which was banned in 1972, was intended for use as a pesticide against disease-bearing insects. It was heavily used for many years and eventually it was found that wildlife, especially bird populations were drastically diminished due to consumption of DDT tainted fish [38].
The overall fertility rate of women aged 15–44 years in the United States dropped 44% between 1960 and 2002 [121]. Lifestyle choices may have been a major contributor of this decline as this study included all women in this age group. However, according to the data from the National Survey for Family Growth, the ‘impaired fecundity rate’ was increased from 11% to 15% between 1982 and 2002 [117]. Furthermore, the incidence of female reproductive disorders such as early puberty, irregular menstrual cycles, endometriosis, premature ovarian failure, and polycystic ovarian disorder is increasing in parallel with the increasing number of EDCs in the environment [63].
Human epidemiological studies suggest that there is a clear association between developmental EDC exposure and adverse health outcomes in females. For example, high maternal serum concentration of p′p′-DDT significantly reduces the probability of pregnancy for their daughters [54]. In addition, there is an association between potential exposure to other EDCs, such as bisphenol A (BPA) and genistein and female reproductive problems. Levels of BPA in blood are associated with a variety of conditions in women including endometrial hyperplasia, recurrent miscarriages, sterility, and polycystic ovary syndrome (PCOS) [240], [333], [335]. An example is that of the inverse correlation between the levels of BPA in urine of women undergoing infertility treatment with the number of eggs recovered in in vitro fertilization (IVF) clinics and serum estradiol levels [219]. High BPA exposure is also associated with chromosomal abnormalities [349]. More alarming recent evidence suggests that there is an association between intrauterine and early life exposure to soy formula and uterine fibroids in adulthood [71]. The same study also showed a similar association between in utero diethylstilbestrol (DES) exposure and fibroids.
Direct evidence from unintentional human exposure to EDCs and observations with wildlife species or lab animals shows that developmental exposure to EDCs singly or in mixtures can cause similar types of consequences as described above [115], [116], [143], [155], [176], [229]. Further evidence from lab animal studies for the effects of developmental exposure to EDCs on the female reproductive system is provided in Section 4. The importance of epigenetics (vs. genetics) in disease susceptibility and phenotypic differences are becoming very clear [99], [161], [178], [341]. Epigenetic mechanisms that play a role in the delayed effects of developmental exposure to EDCs are also presented in Section 4 and Table 1. From a public health perspective, the most serious concern emerging from these studies is that developmental exposure to adverse environmental EDCs may lead to effects in subsequent generation(s) via epigenetic mechanisms, broadly termed transgenerational epigenetic effects (see Section 5 for more details).
Section snippets
Epigenetics
The term “epigenetics” was first introduced in the 1940s by Conrad H. Waddington to describe the developmental program where genes determine the individual’s phenotype and internal and external environmental cues are also taken into consideration [152], [133]. Although the word epigenetic was originally derived from an older terminology “epigenesis” – referring to an embryological concept, it literally means “beyond or above genetics” [332]. However, the current use of the term is somewhat
Development of female reproductive system
Successful female reproductive function requires three components that work in close communication with each other: the ovary, the neuroendocrine system or hypothalamus pituitary gonadal (HPG) axis, and the reproductive tract, including the uterus and oviduct. Therefore, EDC exposure that can affect any one these components can impact the others as well. A recent review provides in-depth information on ovarian development and function and on the factors that play a role in these processes [89].
EDCs and their effects on the female reproductive system
In this section, we focus on selected EDCs, methoxychlor (MXC), DES, genistein, and BPA that have been shown in recent animal studies to adversely affect the female reproductive system, especially through epigenetic mechanisms (Table 1). Some of these effects are transgenerational as well (see Section 5). Each EDC section was organized in the following order: brief description of the EDC, human epidemiological studies, experimental animal studies, physiological effects on the ovary, HPG, and
Transgenerational epigenetic effects of EDCs
Transgenerational epigenetic effects, including those that are induced by EDCs have been discussed in recent reviews [297], [356]. Epidemiological studies have suggested that transgenerational epigenetic effects occur in humans. In the Dutch famine of the 1944, not only did the fetuses that were exposed to under-nutrition in utero suffer from cardiovascular or metabolic disorders during their adulthood, but the grand-children also showed a lower birth weight [199]. In an independent study, an
Conclusions and future directions
Data from the reviewed studies collectively suggest that perinatal EDC exposure affects adult ovaries and female reproductive tissues, leading to reproductive dysfunction, supporting the DoHAD concept. In addition, these effects are mediated primarily by steroid hormone receptors, especially the ERs: via ERβ in the ovary and ERα in the uterus and perhaps both in the hypothalamus and pituitary [7], [60], [153], [156], [358]. Furthermore, most of the EDCs discussed in this article lead to MOF (a
Acknowledgments
The authors wish to thank Dr. Kathy Manger for her assistance in the preparation of this manuscript. The research results from our laboratory described in this review were supported in part by the NIEHS Grant ES013854 and the NIEHS sponsored UMDNJ Center for Environmental Exposures and Disease Grant NIEHS P30ES005022.
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