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

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. KEY WORDS: diethylstilbestrol (DES), endocrine disruptors, fertility rate, fetal and/or neonatal exposure, steroidogenic acute regulatory protein (StAR).

Neonatal Exposure to Diethylstilbestrol Alters Expression of DNA Methyltransferases and Methylation of Genomic DNA in the Mouse Uterus

“…In our previous study, the expressions of Sp1, Sp3 and DNA methyltransferases were increased in the epididymis by DES treatment [10], but in the current study, they were decreased in the uterus. Furthermore, in our previous studies and other reports, body and epididymis weights were decreased by DES treatment in male mice [7,8,25,38], but in the current study using female mice, uterine weights were increased at day 14 although Fig. 4.…”

Dose Paternal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) affect the Sex Ratio of Offspring?

“…In addition, the testis and epididymis of the TCDD-exposed groups exhibited histology with limited influence of TCDD. Thus, even though the major reproductive toxicity induced by TCDD was an impediment to the development of the reproductive organ, the testis and epididymis were considered to function in a normal manner based on histology and the data from our previous study [24].…”

Microarray and gene ontology analyses reveal downregulation of DNA repair and apoptotic pathways in diethylstilbestrol-exposed testicular Leydig cells

“…Because testicular Leydig cells express estrogen receptors (ERs) (Fisher et al, 1997;Saunders et al, 1998), estrogens and estrogenic agents have adverse effects on Leydig cells, such as reduced testicular steroidogenesis (Haavisto et al, 2001;Houk et al, 2004), structural and functional abnormalities (Warita et al, 2006(Warita et al, , 2008Nakamura et al, 2010), and carcinogenic activities (Kurland et al, 1975;Reznik-Schüller, 1979;Deshmukh and Hartung, 1983;Fowler et al, 2000). Diethylstilbestrol (DES) is a synthetic compound with potent estrogenic activity and is generally believed to bind to ERs and mimic the action of the natural estrogen 17β-estradiol (E2).…”