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J. Biol. Chem., Vol. 278, Issue 8, 6470-6481, February 21, 2003
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From the National Institute of Immunology, Aruna Asaf Ali Road,
New Delhi, India 110067
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 Fas-FasL, thus initiating apoptosis in the same
lineage of cells through the activation of the apoptotic pathway chosen
by type II cells.
Diethylstilbestrol Induces Rat Spermatogenic Cell Apoptosis
in Vivo through Increased Expression of Spermatogenic
Cell Fas/FasL System*
*
This work was supported by grants to the National Institute
of Immunology from the Department of Biotechnology, Government of
India.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Fax:
91-11-616-2125; E-mail: cshaha@nii.res.in.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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