Effects of Prenatal Nicotine Exposure on Primate Brain Development and Attempted Amelioration with Supplemental Choline or Vitamin C: Neurotransmitter Receptors, Cell Signaling and Cell Development Biomarkers in Fetal Brain Regions of Rhesus Monkeys

Abstract

Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.

Interrelations between maternal smoking during pregnancy, birth weight and sociodemographic factors in the prediction of early cognitive abilities

“…For example, several studies have shown lower autonomic arousal and vigilance levels in children of mothers who smoked during pregnancy (Horne, Franco, Adamson, Groswasser, & Kahn, 2004;Kristjansson et al, 1989;Raine, 2002). Measures of arousal and vigilance might be specifically sensitive to prenatal smoking, because without continued nicotinic intake after birth, the increased number of nicotinic cholinergic receptor binding sites that have been formed as a consequence of in utero-nicotine exposure may be understimulated (Oncken et al, 2003;Raine, 2002;Slotkin et al, 2005). …”

Maternal prenatal smoking, parental antisocial behavior, and early childhood physical aggression

“…Functional polymorphisms in these genes have been associated with aggressive antisocial behavior (Davidge et al, 2004;Volavka, Bilder, & Nolan, 2004). Exposure to nicotine and carbon monoxide has also been shown to affect catecholaminergic and serotonergic neuromodulation (Slotkin et al, 2005;Xu, Seidler, Ali, Slikker, & Slotkin, 2001). The fact that a genetic predisposition toward antisocial behavior and smoking during pregnancy seem to result in similar neurobiological changes in the central nervous system might increase the likelihood that they reinforce each other's impact (Moffitt et al, 2005).…”

“…Testing for such interactions is important both methodologically, because sole use of covariates could mask key effects, and developmentally, because specific combinations of adverse conditions early in life might increase risk for persistent antisocial behavior beyond the simple sum of such risk factors (Raine, 2002). A combination of maternal prenatal smoking and parental antisocial behavior might be particularly harmful (see Moffitt, Caspi, & Rutter, 2005) because they are both associated with hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) abnormalities in offspring (parental antisocial behavior: Brennan et al, 1997;Van Goozen & Fairchild, 2006;maternal prenatal smoking: Horne, Franco, Adamson, Groswasser, & Kahn, 2004;Slotkin et al, 2005). We do not know if maternal prenatal smoking and parental history of antisocial behavior interact in the prediction of offspring physical aggression, but there are some indications prenatal smoking interacts with factors associated with parental antisocial behavior.…”

Lasting Effects of Developmental Dexamethasone Treatment on Neural Cell Number and Size, Synaptic Activity, and Cell Signaling: Critical Periods of Vulnerability, Dose–Effect Relationships, Regional Targets, and Sex Selectivity

“…Since each neural cell contains a single nucleus (Winick and Noble, 1965), the DNA concentration (DNA per unit tissue weight) assesses the cell packing density, whereas the DNA content (DNA per region) gives an index of the total number of cells (Bell et al, 1987;Slotkin et al, 1984;Winick and Noble, 1965). Neuronal growth and the accompanying cell enlargement necessitate a rise in the ratio of total protein/ DNA (Qiao et al, 2003(Qiao et al, , 2004Slotkin et al, 2005) and the formation of neuritic projections elicits a corresponding rise in the contribution of membrane proteins relative to other cell proteins (membrane/total protein ratio). Accordingly, we assessed these indices as well.…”