Proapoptotic effects of lindane on mouse primordial germ cells

Lindane (gamma-HCH) was examined for its effect on primordial germ cell (PGC) development in the mouse embryo. We found that exposure by gavage of pregnant mice to 15 or 30 mg/kg/bw lindane during the period of PGC migration and gonad colonization (from 8.5 to 11.5 days post coitum, dpc) resulted in a significant reduction of the number of germ cells within 12.5 dpc testis and ovaries (a maximum of about 25 and 40%, respectively). Similarly, lindane caused a dose-dependent decrease of the PGC number in an in vitro culture model. Further experiments showed that in such model, lindane induced features of apoptotic cell death in PGCs such as increase in caspase-3 activity, poly-ADP-ribose polymerase cleavage, and terminal dUTP nick-end labeling (TUNEL) positivity. A marked increase of the number of PGCs positive for TUNEL staining was also observed in 12.5 dpc gonads of embryos from pregnant mice subjected one day before to acute lindane treatment (60 mg/kg/bw). Finally, we show that a brief incubation of isolated PGCs with 10(-5)M lindane resulted in a marked decrease of the basal and kit-ligand-induced phosphorylation level of the AKT kinase, known to be crucial for PGC survival. Taken together these results demonstrate that embryo exposure to lindane during early stages of gametogenesis can severely impair the number of germ cells in the fetal gonads; the compound appears to affect PGC survival through a direct proapoptotic action likely resulting from its adverse effect on AKT activity in such cells.