Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4231, USA
Address for correspondence: Michael K. Skinner, Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4231. Voice: 509-335-1524; fax: 509-335-2176. Skinner{at}mail.wsu.edu
The molecular and cellular control of embryonic testis development
was investigated through an analysis of the embryonic testis
transcriptome to identify potential regulatory factors for male
sex determination and testis morphogenesis. One critical factor
identified is neurotropin 3 (NT3). At the onset of male sex
determination, Sertoli cells initiate differentiation and express
NT3 to act as a chemotactic factor for mesonephros cells to
migrate and associate with Sertoli-germ cell aggregates to promote
cord formation. Promoter analysis suggests that NT3 may be an
initial downstream gene to SRY and helps promote testis morphogenesis.
Endocrine disruptors were used to potentially interfere with
embryonic testis development and further investigate this biological
process. The estrogenic pesticide methoxychlor and antiandrogenic
fungicide vinclozolin were used. Previous studies have shown
that methoxychlor and vinclozolin both interfere with embryonic
testis cord formation and cause increased spermatogenic cell
apoptosis in the adult testis. Interestingly, transient
in vivo exposure to endocrine disruptors at the time of male sex determination
caused a transgenerational phenotype (F1-F4) of spermatogenic
cell apoptosis and subfertility. This apparent epigenetic mechanism
involves altered DNA methylation and permanent re-programming
of the male germ-line. A series of genes with altered DNA methylation
and imprinting are being identified. Observations reviewed demonstrate
that a transient embryonic
in utero exposure to an endocrine
disruptor influences the embryonic testis transcriptome and
through epigenetic effects (e.g., DNA methylation) results in
abnormal germ-cell differentiation that subsequently influences
adult spermatogenic capacity and male fertility, and that this
phenotype is transgenerational through the germ-line. The novel
observations of transgenerational epigenetic endocrine disruptor
actions on male reproduction critically impact the potential
hazards of these compounds as environmental toxins. The literature
reviewed provides insight into the molecular and cellular control
of embryonic testis development, male sex determination, and
the programming of the male germ-line.
