The effect of prenatal nicotine exposure on PDGFR-mediated anti-apoptotic mechanism in the caudal brainstem of developing rat.

Maternal cigarette smoking is a major risk factor for sudden infant death syndrome (SIDS); however, the mechanism underlying this association is currently unknown. Prenatal nicotine exposure is accompanied by a decrease in the magnitude of hypoxic ventilatory depression, the component of hypoxic ventilatory response that activates the PDGF-beta receptor (PDGFR) and its downstream anti-apoptotic cascade in the caudal brainstem (CB) of developing rats. In this study, we evaluated the effect of prenatal nicotine exposure on PDGFR activation and the subsequent activation of downstream anti-apoptotic processes through the Akt/BAD pathway. The 5-day timed-pregnant Sprague-Dawley rats underwent surgical implantation of an osmotic pump containing either normal saline (control) or a solution of nicotine tartrate. The CB was harvested from 5-day-old rat pups (n=8-10 for each time point) in each group after exposure to normoxia or hypoxic challenges with 10% O(2) for 5, 15, 30, 60 or 120 min. Immunoprecipitation and immunoblots of CB lysates revealed phosphorylation of PDGFR, Akt and BAD-136 during hypoxia in control pups. Prenatal nicotine exposure was associated with attenuation of these responses at all time points. Analysis of an early apoptotic marker in the CB revealed that activation of cleaved caspase-3 occurred only at 120 min of hypoxic exposure in the control. Prenatal nicotine exposure accelerated this response, causing early activation at 30 and 60 min. We conclude that prenatal nicotine exposure attenuates the phosphorylation of PDGFR, Akt and Bad-136 during hypoxia in the CB of developing rats. This modulation of anti-apoptotic cascades accelerates activation of the early apoptotic marker. We speculate that prenatal nicotine exposure affects apoptosis in the CB of developing animals and may increase the vulnerability of neural cells in the respiratory control area, a process that may underlie the association between maternal smoking and SIDS.