Effects of Estrogenic Chemicals on Accessory Reproductive Organs Interaction with Endogenous Androgens

The period of differentiation of the accessory reproductive organs varies from species to species. In long-gestation mammals, such as humans and pigs, differentiation of reproductive organs occurs primarily during prenatal life, although some aspects of sexual differentiation may occur after birth. In species with a very short gestation length, such as the mouse (18-19 days) and rat (21-23 days), gonadal and secondary sexual differentiation begins during the middle of gestation and continues into postnatal life for varying periods of time for different organs [161].

Between the seventh and eighth week of gestation in humans, stromal tissue in the developing testes derived from mesenchyme differentiates into the steroid secreting Leydig cells, which are located in the interstitial area between the seminiferous cords [162]. The Leydig cells rapidly begin secreting testosterone [163], the primary androgen secreted by testes in fetuses as well as adults. In addition, Mullerian inhibiting hormone (MIH), a glycoprotein, is secreted by the Sertoli cells and acts locally to suppress the development of the ip-silateral Mullerian duct [164,165], and may also be involved in testicular development [166].

The secretion of androgen by the fetal testes is a necessary prerequisite to masculinization of the accessory reproductive organs, external genitalia, liver, kidney, and brain in males; in the liver, kidney, genitals, and brain, an important effect of androgen is the "imprinting" of enzyme systems that markedly influence tissue function and, more generally, homeostasis, throughout the remainder of life [1]. Without the secretion of androgen by the fetal testes, the secondary sexual characteristics are those typical of females. However, there is also evidence that estrogen plays an important role in the normal processes of mas-culinization of the brain and accessory reproductive system [161,167,168]. As a result, EDCs that interfere with the normal activity of either androgen or estrogen can disrupt the processes mediating the differentiation of accessory reproductive organs in males; these include the efferent ducts, epididymides, vas deferens, and seminal vesicles, which differentiate from the Wolffian (mesonephric) ducts under the local (not systemic) action of testosterone. In contrast, circulating testosterone mediates the differentiation of the external genitals and the urethra and associated glands, including the prostate and other periurethral glands; in rodents these include preputial glands which release pheromones involved in regulating social behaviors. These organs develop from tissues in the embryonic urogenital sinus and perineum and express the enzyme 5a-reductase during fetal (and in rodents also neonatal) life and differentiate under the control of 5a-dihydrotestosterone (DHT). Testosterone in the systemic circulation serves as the substrate for 5a-reductase rather than diffusion of testosterone from the ipsilateral testis, which controls differentiation of only the adjacent Wolffian duct.

The importance of the conversion of testosterone to DHT in selected target tissues is that DHT is as much as ten times more potent relative to testosterone [169]. Thus, while testosterone levels in the circulation are too low to induce differentiation of the Wolffian ducts without supplemental diffusion from the adjacent testis, 5a-reductase serves to amplify the action of testosterone in tissues by virtue of converting testosterone into the more potent DHT. Any chemical that interferes with the action of 5a-reductase will thus profoundly alter the differentiation of organs that express this enzyme during sexual differentiation [161].

This information is relevant to this discussion, since estrogen exerts an inhibitory effect on 5a-reductase and other steroid metabolizing enzymes, such as 17a-hydroxylase, which is involved in androgen biosynthesis [170].When exposure occurs during fetal and neonatal life in rats, this effect is permanently imprinted in cells [171]. Both enzyme activity and steroid binding in male accessory reproductive organs are highly sensitive to the permanent, organizational effects of estrogen during fetal life [155,167,172].

In a number of studies involving BPA (e.g., see above), opposite effects of es-trogenic chemicals have been observed on organs which differentiate from the urogenital sinus (prostate and preputial glands) relative to effects on organs which differentiate from the Wolffian ducts (epididymides and seminal vesicles). While such findings might appear confusing or contradictory, it is not unexpected that chemicals will exert different effects on embryonic tissues in which the hormonal mechanisms regulating differentiation differ.

Studying the (permanent) effects of fetal exposure to estrogenic chemicals on the brain (and behavior) and reproductive organs (preputial glands, prostate, seminal vesicles, epididymides, and testes) of mice increases insight into the multiple mechanisms by which EDCs act in different species. In mice, for example, preputial gland pheromones are involved in social communication between males and females [173] and influence aggressiveness between males [174,175]. Preputial gland secretions pass through ducts which empty into the prepuce, which is specially adapted in mice for depositing urine marks [176]. The placing of these pheromones into a male mouse's environment via urine marking behavior is influenced by dominance status; dominant males mark at high rates, and subordination inhibits this behavior [177]. Fetal exposure to very low doses, within an environmentally relevant range, of estrogenic chemicals such as o,p'-DDT, increases preputial gland size and the rate at which male mice deposit urine marks in a novel environment [171],as well as inter-male aggressiveness [178]. This suggests that environmental estrogens may influence brain development and socio-sexual behaviors, as well as alter the functioning of organs involved in socio-sexual communication. In addition, these same chemicals can alter sperm development, sperm motility, and enzymes essential for fertilization. They may also alter the functioning of sperm after they are deposited in the female reproductive tract, for example by altering the functioning of the seminal vesicle and prostate glands that produce the components of seminal fluid [26,179-181].

Differences and similarities in molecular systems across species are not well known, including species differences in the response to estrogens. However, at the receptor level, there is little evidence for significant differences between vertebrate species in the affinity of estradiol for estrogen receptors [182]. Therefore, if estradiol (and potentially other estrogenic chemicals) reaches estrogen receptors in target cells, the capacity to generate responses may not be very different among vertebrate species, although specific responses will vary not only between species, but within a species, as a function of age.

While the response of breast cancer cells and tissues in rodents and humans to estrogen appears to be very similar [183], comparisons of the sensitivity of different species to estrogenic chemicals are still needed. However, it is likely that individual differences in the response to estrogens as well as species differences are not mediated by differences in affinity of ligands for either the alpha or beta form of the estrogen receptor. Instead, such differences may be mediated by events that occur after a chemical has bound to the receptor, and these intermediate events are different in different target tissues [184].

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