Testicular Stem Cell Dysfunction Due to Environmental Insults Could Be Responsible for Deteriorating Reproductive Health of Men.

ABSTRACT

Reproductive health of men has declined over time including reduced semen quality specifically sperm count, increased incidence of infertility, and testicular cancers. Our recent findings suggest that these disease states possibly arise as a result of disruption of testicular stem cells biology by perinatal insults including exposure to endocrine disrupting chemicals. Testicular stem cells include relatively quiescent, very small embryonic-like stem cells (VSELs), and actively dividing spermatogonial stem cells (SSCs). Both VSELs and SSCs express estrogen receptors and are directly vulnerable to endocrine disruption. Exposing mice pups to estradiol (20 µg/pup/day on days 5-7) or diethylstilbestrol (2 µg/pup/day on days 1-5) affected spermatogenesis during adult life with reduced numbers of tubules in stage VIII, tetraploid cells and sperm. These mice were infertile and majority of diethylstilbestrol treated mice revealed testicular cancer-like changes. An increase in VSEL numbers, observed by both flow cytometry and qRT-PCR, was associated with marked reduction of c-KIT positive spermatogonial cells. VSELs undergo epigenetic changes due to endocrine disruption that results in blocked differentiation (impaired spermatogenesis) leading to reduced sperm count and infertility, and their excessive self-renewal initiates cancer-like changes in adult life. Thus, testicular dysgenesis syndrome (TDS) has a stem cell rather than a genetic basis.