Differential effects between developmental and postpubertal exposure to N-methyl-N-nitrosourea on progenitor cell proliferation of rat hippocampal neurogenesis in relation to COX2 expression in granule cells.

This study was performed to compare the exposure effects of N-methyl-N-nitrosourea (MNU), a cytocidal agent of proliferating cells, on rat hippocampal neurogenesis between developmental and postpubertal periods. Developmental exposure through maternal drinking water from gestational day 6 to day 21 after delivery on weaning decreased GFAP-immunoreactive (+) stem cells and increased immunoreactive cells indicative of subsequent progenitor and postmitotic immature neuronal populations, TUNEL+ or p21Cip1/Waf1+ stem/progenitor cells and COX2+ granule cells, on postnatal day (PND) 21. On PND 77 after cessation of developmental exposure, NeuN+ postmitotic granule cells decreased in number. Postpubertal exposure by oral gavage for 28days decreased the numbers of all granule cell lineage populations and ARC+ or COX2+ granule cells and increased the number of TUNEL+ stem/progenitor cells. These results suggested that both developmental and postpubertal exposure caused apoptosis of stem/progenitor cells. However, developmental exposure increased COX2 expression to facilitate intermediate progenitor cell proliferation and increased neuronal plasticity. This effect was concurrent with the induction of p21Cip1/Waf1 that causes cell cycle arrest of stem/progenitor cells in response to accumulating DNA damage on weaning, resulting in a subsequent reduction of postmitotic granule cells. In contrast, postpubertal exposure suppressed neuronal plasticity as evidenced by downregulation of ARC and COX2. The COX2 downregulation was responsible for the lack of facilitating stem/progenitor cell proliferation. Induction of apoptosis and the lack of cell proliferation facilitation may be responsible for the overall reduction of neurogenesis caused by postpubertal exposure. Thus, the disrupted pattern of hippocampal neurogenesis induced by MNU is different between developmental and postpubertal exposure.