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

Abstract

For the purpose of investigation of working mechanisms in endocrine disruptors, we evaluated the dose-related effects of fetal and/or neonatal exposure to an estrogenic compound on the male reproductive organs in adult mice, particularly with respect to gene expression of steroidogenic acute regulatory protein (StAR). The pregnant ICR mice were given subcutaneous injections of 10 μg/day/animal of diethylstilbestrol (DES) to subject the fetal mice to in utero exposure (IUE). Subsequently, the newborn male mice were subjected to neonatal exposure (NE) by treatment with vehicle or 0.1-10 μg/day/animal of DES. Fertility rates of each group were as follows: control, 100%; IUE only, 60%; IUE+NE 0.1 μg, 25%; IUE+NE 1 μg, 0%; IUE+NE 10 μg, 0%. In general histology, germ cell layers in the seminiferous tubules were thinned in the group of IUE+NE 10 μg. Hypoplasia of the Leydig cells, in which the staining intensity of eosin was diminished, was also observed in the groups of IUE+NE 0.1-10 μg. The androgen receptor (AR) and estrogen receptor alpha (ERα) immunoexpression in the Leydig cells of IUE+NE 1-10 μg was slightly lower than that in the controls. Longterm dysfunction of the hypothalamo-pituitary-testicular axis, including sustained hypoproduction of gonadotropin and testosterone, and altered expressions of steroid hormone receptors and StAR genes were observed. The hypothalamo-pituitary control of gonadotropin secretion may be affected by the smaller doses of estrogenic agents than the reproductive organs. Furthermore, the fertility rate in the male mice exposed to this estrogenic agent was closely correlated with the testosterone levels, and even more so with the rate-limiting factor of steroidogenesis, StAR. This finding suggests that endocrine disruptors have an important pronounced effect on StAR gene expression.