Fetal and perinatal influence of xenoestrogens on testis gene expression.

The incidence of reproductive abnormalities in the male has been reported to have increased during the past 50 years. It has been suggested that these changes may be attributable to the presence of chemicals with oestrogenic activity in our environment. The aim of the experiments described in this chapter was to investigate the effects of acute exposure to high levels of xenoestrogens either indirectly during fetal life, or directly during neonatal life, on gene expression in the testis and pituitary. Fetal treatment involved administration of diethylstilbestrol (DES), 4-octylphenol (OP) or vehicle (oil, control) to pregnant rats on days 11.5 and 15.5 post coitum; fetuses were recovered on day 17.5. There was no difference between fetuses from control and treated mothers in either the overall histology of the testes or numbers of Leydig cells as determined by immunohistochemistry with an antibody directed against 3 beta-HSD. However there was a consistent and striking reduction in the amount of P450 17-a hydroxylase C17, 20 lyase (P450c17) and steroidogenic factor 1 (SF-1) detected by immunocytochemistry in testes from treatment groups given the higher doses of OP and DES. Oestrogen receptors (ER alpha) were present in the fetal leydig cells of all animals. Neonatal treatment involved direct injection of oil (control), DES, OP or Bisphenol A (Bis A) on days 2, 4, 6, 8, 10 and 12; pituitaries and testes were recovered on day 18. Testis weights and seminiferous tubule diameters were significantly reduced in animals treated with DES. In these same animals immunocytochemical localisation revealed that the amounts of FSH beta subunit and inhibin alpha subunit were reduced in their pituitaries and testes respectively. OP did not appear to have an acute, measurable effect on testis gene expression but a reduction in testis weight was noted in adult animals given the same treatment regime. The effects observed are consistent with negative feedback by oestrogens on pituitary production of FSH resulting in retarded maturation of seminiferous tubules and reduced Sertoli cell numbers. These studies have demonstrated that administration of high levels of oestrogens can affect gene expression in the testis early in life. However, the relevance of these findings to observations in man await a) a greater understanding of the physiological role(s) of oestrogens in normal males, b) an evaluation of the sources, routes of exposure, concentrations in vivo and bioavailability of xenoestrogens.