Diethylstilbestrol Induces Rat Spermatogenic Cell Apoptosis in Vivo through Increased Expression of Spermatogenic Cell Fas/FasL System

Abstract

The significant role that estrogens play in spermatogenesis has opened up an exciting area of research in male reproductive biology. The realization that estrogens are essential for proper maintenance of spermatogenesis, as well as growing evidence pointing to the deleterious effects of estrogen-like chemicals on male reproductive health, has made it imperative to dissect the role estrogens play in the male. Using a model estrogen, diethylstilbestrol (DES), to induce spermatogenic cell apoptosis in vivo in the male rat, we provide a new insight into an estrogen-dependent regulation of the Fas-FasL system specifically in spermatogenic cells. We show a distinct increase in Fas-FasL expression in spermatogenic cells upon exposure to diethylstilbestrol. This increase is confined to the spermatid population, which correlates with increased apoptosis seen in the haploid cells. Testosterone supplementation is able to prevent DES-induced Fas-FasL up-regulation and apoptosis in the spermatogenic cells. DES-induced germ cell apoptosis does not occur in Fas-deficient lpr mice. One other important finding is that spermatogenic cells are type II cells, as the increase in Fas-FasL expression in the spermatogenic cells is followed by the cleavage of caspase-8 to its active form, following which Bax translocates to the mitochondria and precipitates the release of cytochrome c that is accompanied by a drop in mitochondrial potential. Subsequent to this, activation of caspase-9 occurs that in turn activates caspase-3 leading to the cleavage of poly(ADP-ribose) polymerase. Taken together, the data indicate that estrogen-like chemicals can precipitate apoptotic death in spermatogenic cells by increasing the expression of spermatogenic cell FasFasL, thus initiating apoptosis in the same lineage of cells through the activation of the apoptotic pathway chosen by type II cells.

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations

“…Previous studies reported that exposure to non-physiological concentrations of estrogen, testosterone, and estrogenlike chemicals could stimulate the apoptotic pathway in animal germinal cells (Zhou et al 2001, Kim et al 2003, Nair & Shaha 2003, Jung et al 2004, Mishra & Shaha 2005, and cause DNA damage in human sperm (Anderson et al 2003). These reports support the correlations we observed for the European men, e.g.…”

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

“…In the GO classification, "apoptotic program" is a subcategory of "cell death" and refers to a form of programmed cell death. It has been reported that exposure to DES induces germinal cell apoptosis in male rodents (Nonclercq et al, 1996;Nair and Shaha, 2003;Ma et al, 2008); however, our results suggest that DES provides Leydig cells with an intracellular environment in which it is difficult to trigger apoptosis. Meanwhile, "DNA repair" is a subcategory of "DNA metabolism," which is the high-ranked GO term decreased in the DES-treated cells.…”

Effects of Maternal Exposure to a Low Dose of Diethylstilbestrol on Sexual Dimorphic Nucleus Volume and Male Reproductive System in Rat Offspring

“…The administration of DES to newborn or mature rats has been reported to increase germ cell apoptosis (Atanassova et al, 2000;Nair and Shaha, 2003). On the other hand, it has been reported that the administration of DES to adult rats does not influence spermatogenesis or sperm morphology (Goyal et al, 2001), and that DES administration increases FSH levels, promoting spermatogenesis (Atanassova et al, 1999).…”