Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo

Methylmercury (MeHg) is recognized as a significant environmental hazard, p articularly to the development of the nervous system. To study the molecula r mechanisms underlying cell cycle inhibition by MeHg, we assessed the invo lvement of p21 (Waf1, Cip1), a cell cycle regulatory gene implicated in the G(1) and G(2) phases of cell cycle arrest, in primary embryonic cells and adult mice following MeHg exposure. Previous literature has supported the a ssociation of increased p21 expression with chondrocyte differentiation. In support of this finding, we observed an increasing p21 expression during l imb bud (LB), but not midbrain central nervous system (CNS) cell differenti ation. Both embryonic LB and CNS cells responded to MeHg exposure with a co ncentration-dependent increase in p21 mRNA. In the parallel adult study, C5 7BL/6 female mice were chronically exposed to 10 ppm MeHg via drinking wate r for 4 weeks. While there was limited or absent induction of Gadd45, Gadd1 53, and the gamma-glutamylcysteine synthetase catalytic subunit, p21 was ma rkedly induced in the brain, kidney, and liver tissues in most of the anima ls that showed MeHg-induced behavioral toxicity such as hyperactivity and t remor. Furthermore, the induction of p21 mRNA was accompanied by an increas e in p21 protein level. The results indicate that the activation of cell cy cle regulatory genes may be one mechanism by which MeHg interferes with the cell cycle in adult and developing organisms. Continued examination of the molecular mechanisms underlying cell cycle inhibition may potentially lead to utilization of this mechanistic information to characterize the effects of MeHg exposure in vivo. (C) 1999 Academic Press.