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Fertility Alterations Related to Endocrine Disruptors
Introduction
The objective of this essay is to review the endocrine disruptors’ effects on the reproductive system, and whether it is a clinical concern in domestic animals. We will discuss the physiological effects in male and female animals, and dive deeper into the concerns related to different species. The ways of exposure and accumulative capacities of the endocrine disruptors will also be taken into consideration.
Table of Content
Endocrine Disruptors
Endocrine disruptors (ED) are defined as substances found in our environment with the ability to alter the physiology of the mammalian or avian endocrine system. Both adult animals and developing organisms may experience harmful and long-lasting damage. Among these are developmental disorders, altered metabolic balance and reproductive problems. There is a broad spectre of ways of exposure, and they have an effect in really small doses. The endocrine disruptors may be incorporated orally, penetrate through skin or through mucous membranes. Offspring may receive disruptors through the placenta, with breast milk or into an egg. They are found in minerals (e.g. lead, mercury), micotoxins (e.g. zearalenon), agriculture (e.g. insecticides), industry (e.g. phthalates, BPA), among others (see Figure 1).
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The endocrine disruptors may disturb the hypothalamic-pituitary-thyroid, hypothalamic-pituitary-gonad and hypothalamic-pituitary-adrenal axis in several ways. They may interfere with the synthesis, release, transport or degradation of hormones, receptors or signalling cascades of target cells, or the hypothalamus itself. The biochemical properties of mitochondria can be affected, as well as altered metabolic rate and gene-expression. In this article, we have chosen to focus on some of the most common endocrine disruptors eliciting a concerning impact on the male and female reproductive systems.
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Brief Description of Specific Endocrine Disruptors
Methoxychlor (MXC)
Methoxychlor (MXC) is an organochlorine pesticide. It is used as a replacement for DDT, another organochlorine known for its infamous, destructive impact on the environment. MXC metabolites possess estrogenic, anti-estrogenic and anti-androgenic properties (Gaido et al., 2000).
Genistein
Genistein is a flavonoid phytoestrogen found in several plants, including soy beans, medicinal plants, and coffee. It has been proven that genistein possesses estrogenic properties in several mammalian species. (Whitehead et al., 2002).
Bisphenol A (BPA)
Bisphenol A (BPA) is a man-made monomer used to produce polycarbonate plastic and epoxy resins (Markey et al. 2002). Many studies have shown that BPA possess estrogenic properties, likely due to shared similarities in their chemical structure (indicated in Figure 3). It is to be found in i.e. plastic bottles, food containers and animal cages and has been spread to the environment through these common objects. Consequently, it proposes a huge potential health risk concerning, among several aspects, mammalian reproduction (Hunt et al., 2003).
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Vinclozolin
Vinclozolin is a fungicide, commonly used to control diseases on fruits, berries and vegetables. In addition, it is used on the turf on golf courses. Vinclozolin has known anti-androgenic activity (Kelce et al., 1994).
DDE
Dichlorodiphenyldichloroethylene (DDE) is a common breakdown product from DDT. Due to the extensive utilization of DDT and DDE in society and agriculture during the 1900’s, they are still widely found in animal tissue samples. DDE is especially concerning as it is rarely excreted from the body once it’s consumed. The exception is breast milk, indicating that accumulation in infants commence almost directly post-partum. Less research is conducted on DDE’s impact on the reproductive system in mammals. However, it is proven to possess anti-androgenic effects (Andersen et al., 2002).
Effects on female fertility
Concerning endocrine disruptors’ alterations on the female reproductive system, they will execute their effect at the level of ovarian development and function, which can lead to reproductive abnormalities in adult life and, at worst, be transgenerational (Uzumcu et al. 2006). The primary ovarian function in an adult is to produce hormones needed for (1) folliculogenesis (ovarian development), (2) ovulation, and (3) the initiation and maintenance of mammalian pregnancy. The initial phase of folliculogenesis includes the formation of primordial follicles and follicular transition (conversion of follicle from primordial to primary) (McGee et al. 2000), and is regulated and influenced by steroid hormones, such as progesterone, androgens, and estrogens. This is significant because several environmental endocrine disruptors elicit their effect through estrogenic receptors found throughout the reproductive tract: ER-α and ER-β. ER-α is found in the uterus, whilst ER-β is present in both the fetal testis and ovary (Anway et al. 2006). In experiments conducted to investigate the role of endocrine disruptors’ effect on female fertility, oocytes, theca-, and granulosa cells have been utilized (Magnusson et al. 2015).
Estrogenic endocrine disruptors
Methoxychlor (MXC)
In vivo studies where rats were under chronic exposure of MXC, accelerated vaginal opening, early onset of the first estrus and reduced fertility were detected (Gray et al. 1989). By increasing the dosage of MXC, females showed continuous estrus. As a result, they were unable to get pregnant, even though they mated. In the same study, it was also proven that MXC exhibit transgenerational effects: the females off-springs (F1) suffered from irregular cycles with reduced fertility and had an earlier reproductive senescence than the control group. Within antral follicles, in vitro studies have shown that MXC induces atresia. This is mediated by mechanisms such as oxidative stress and ER-mediated pathways (Uzumcu et al. 2006). MXC also affects granulosa cells directly by inhibiting basal-, FSH-, and estradiol (E2)-stimulated progesterone secretion. However, no effect was detected on cAMP levels (Chedrese et al. 2001).
Genistein
In studies where genistein was administered to mice, accelerated vaginal opening and irregular estrus cycles were revealed. The highest dose of genistein given during the study resulted in infertility. It adversely affected the fertilizability and developmental capacity of fertilized oocytes to the blastocyst stage, resulting in a multi-oocyte follicle (MOF) phenotype (Nagao et al. 2001). Within rat ovarian follicles, genistein blocks LH-induced ovulation and testosterone production and decreases cAMP levels, yet it does not affect E2-synthesis. Genistein has shown similar properties to MXC concerning its effect on granulosa cells. However, it does not alter E2-accumulation (Uzumucu et al. 2006). Bisphenol A (BPA) Developmental exposure to BPA is connected to several abnormalities concerning female fertility. It induces early vaginal opening, early first – as well as irregular – estrus cycles, and MOF. This is directly related to reduced fertility and early reproductive senescence, as well as later instances of pathology. (Markey et al. 2002) In contrast to MXC and genistein, PBA stimulates basal and FSH-induced progesterone production. Nevertheless, it will inhibit FSH-stimulated E2-secretion in granulosa cells (Uzumucu et al. 2006).
Anti-androgenic endocrine disruptors
Vinclozolin
Vinclozolin has been reported to induce changes on the normal pattern of sexual differentiation and sexual function in the adult. In addition, it possesses transgenerational effects. When given orally to 7-week-old female rats, it resulted in disturbances of development of the sex organs. In adult rats, a prolonged estrus cycle duration was indicated, being a result of alterations of the LH and E2:testosterone ratio in the serum(Shin et al. 2006). Analysis of in utero effects of vinclozolin exposed a masculinization of female embryos (Uzumucu et al. 2006).
DDE
DDE has been shown to alter the ovarian steroidogenesis (synthesis of steroid hormones). This may affect fertility negatively. In granulosa cells, DDE inhibits basal and FSH-induced progesterone secretion and cAMP production. Nevertheless, it will stimulate cell proliferation (Chedrese et al. 2001).