Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man

Abstract

The effects on reproductive tract development in male rats, of neonatal exposure to potent (reference) oestrogens, diethylstilboestrol (DES) and ethinyl oestradiol (EE), with those of two environmental oestrogens, octylphenol and hisphenol A were systematically compared. Other treatments, such as administration of a gonadotrophin-releasing hormone antagonist (GnRHa) or the anti-oestrogen tamoxifen or the anti-androgen flutamide, were used to aid interpretation of the pathways involved. All treatments were administered in the neonatal period before onset of puberty. The cellular sites of expression of androgen receptors (AR) and of oestrogen receptor-alpha (ERalpha) and ERbeta were also established throughout development of the reproductive system. The main findings were as follows: (i) all cell types that express AR also express one or both ERs at all stages of development; (ii) Sertoli cell expression of ERbeta occurs considerably earlier in development than does expression of AR; (iii) most germ cells, including fetal gonocytes, express ERbeta but not AR; (iv) treatment with high, but not low, doses of potent oestrogens such as DES and EE, induces widespread structural and cellular abnormalities of the testis and reproductive tract before puberty; (v) the latter changes are associated with loss of immunoexpression of AR in all affected tissues and a reduction in Leydig cell volume per testis; (vi) none of the effects in (iv) and (v) can be duplicated by treating with high-dose octylphenol or bisphenol A; (vi) none of the reproductive tract changes in (iv) and (v) can be induced by simply suppressing androgen production (GnRHa treatment) or action (flutamide treatment); and (vii) the adverse changes induced by high-dose DES (iv and v) can be largely prevented by co-administration of testosterone. Thus, it is suggested that many of the adverse changes to the testis and reproductive tract induced by exposure to oestrogens result from a combination of high oestrogen and low androgen action. High oestrogen action or low androgen action on their own are unable to induce the same changes.

Interactions of methoxyacetic acid with androgen receptor

“…However, our finding that MAA potentiates AR transcriptional activity even in the presence of potent coactivators of AR suggests that this potentiation proceeds by a mechanism that is independent of these coactivators. Since the balance between androgens and estrogens is critical for normal testicular development (Sharpe et al, 1998) and adult male reproductive behavior (Williams et al, 2001), any disturbance of this balance caused by MAA could potentially be harmful and may contribute to testicular toxicity. AR plays a critical role in male sexual development, and the expression of several genes in the testes is dependent upon appropriate levels of AR signaling (Zhou et al, 2005;Eacker et al, 2007).…”

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

“…Previous studies have shown that fetal and/or neonatal treatment of rodents with DES induces adverse changes similar to those that occur after administration of estradiol-17β [1,10,34], dichlorodiphenyl trichloroethane (DDT) and methoxychlor (an estrogenic pesticide currently used as a substitute for DDT) [14,38]. It is suggested that many of the adverse changes to the testis and reproductive tract induced by exposure to estrogens result from a combination of high estrogen and low andro-gen activity [39]. ER-knockout mice [9], in which the form of the ER is inactivated, are infertile because of impaired fluid resorption from the efferent ducts [12].…”

Effects of daidzein on testosterone secretion in cultured immature mouse testis

“…While lower doses of daidzein have a very weak estrogen-like effect and are not sufficient to influence testosterone production. This hypothesis is supported by experiments that demonstrated that exposure of neonatal rats to high doses of octylphenol and bisphenol A (weak estrogens) had no side effects on testis and contrarily increased testosterone production and simulated the effects of low doses of diethylstilbestrol on advancing the normal onset of pubertal spermatogenesis [26].…”

“…Many in vivo and in vitro experiments have shown that exposure of fetus and neonate to potent estrogens decreases male testosterone production and causes reproductive system abnormalities [25][26][27]. However, it is worth noting that estrogen concentrations in these experiments are high.…”

“…For example, diethylstilbestrol doses reached several hundred micrograms per kilogram of body weight during in vivo experiments and 4 ×10 -6 M in tissue culture. While lower doses of estrogens can regulate spermatogenesis [28,29], promote the Leydig cell development, and testosterone production [26], daidzein has only weak estrogenic activity and its affinity with estrogen receptors is 10 -3 less than that of estrogen [30,31]. Therefore, the effect of a high dose of daidzein on testosterone production in cultured 3-day-old mouse testis probably simulates lower doses of estrogen.…”