Neuronal migration is transiently delayed by prenatal exposure to intermittent hypoxia

Abstract

BACKGROUND: Neonatal neurodevelopment is influenced by a variety of external factors, although the mechanisms responsible are poorly understood. Prenatal hypoxia, from physiological or chemical sources, can have no discernible effect, or can result in a broad spectrum of abnormalities. METHODS: To mimic some of the maternal effects of smoking, we developed a model that investigates the effects of intermittent hypoxia (IH), with or without concurrent nicotine in timed pregnant Sprague-Dawley rats. RESULTS: We found no significant differences between litter sizes or birthweight of pups from any treatment group, but animals exposed to IH (with or without nicotine) showed long term diminished body weights. Animals subjected to IH consistently showed a transient delay in neuronal migration early in the postpartum period, which was amplified by concurrent nicotine administration. We observed increased c-Abl protein levels in animals from the IH treatment groups. Multiple proteins involved in the intricate control of neuronal migration were also altered in response to this treatment, primarily the downstream targets of c-Abl: Cdk5, p25, and the cytoskeletal elements neurofilament H and F-actin and catalase. Catalase activity and protein levels, already elevated in response to IH, were further amplified by simultaneous nicotine exposure. CONCLUSIONS: This new model provides a novel system for investigating the effects of low grade IH in the developing brain and suggests that concurrent nicotine further aggravates many of the deleterious effects of IH. We also describe IH as a previously unreported mechanism for c-Abl expression. Birth Defects Res B 74:287-299, 2005. r 2005 Wiley-Liss, Inc.

Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment

“…Recent evidence suggests that intermittent hypoxia may affect proteins involved in neuronal migration and that nicotine exacerbates this effect [31].…”

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

“…Recent studies using DNA microarrays have shown that gestational nicotine exposure affects gene expression associated with cell adhesion and cell death/survival in the brains of adolescent rats (Cao et al, , 2013Wei et al, 2011). Although the effect of nicotine on neuronal migration has not yet been studied in detail, it has been reported that exposure to nicotine with intermittent hypoxia during gestation inhibited neuronal migration while nicotine alone (without intermittent hypoxia) had no effect (Zechel et al, 2005). These previous results are consistent with our present findings (Figure 2 and Supplementary Figure S1).…”

Interactive Endogenous Small Molecule (Gaseous) Signaling: Implications for Teratogenesis

“…There were corresponding changes in the peroxisomal antioxidant enzyme catalase, as well as the tyrosine kinase c-Abl that has been shown to control both the stability and activity of catalase [291,292]. Cell cycle proteins, Cdk5 and p25, and cytoskeletal proteins, neurofilament H and F-actin, involved in neuronal migration were altered by the hypoxia [290].…”

“…It has been hypothesized that embryos may conserve ATP by reducing cellular proliferation and, consequently, hypoxia may cause growth retardation in embryos [289]. Consistent with this view because cigarette smoking has been shown to induce growth-retarded newborns, a rat model of exposure to intermittent hypoxia has been developed to mimic the effects of smoking [290]. The rat offspring were not found to have decreased weights at birth, but developed long term diminished body weights and transient delay in neuronal migration during the neonatal period.…”