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.
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.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Frederic J
FJ
Seidler
Dan
D
Qiao
Justin E
JE
Aldridge
Charlotte A
CA
Tate
Mandy M
MM
Cousins
Becky J
BJ
Proskocil
Harmanjatinder S
HS
Sekhon
Jennifer A
JA
Clark
Stacie L
SL
Lupo
Eliot R
ER
Spindel
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D002794:Choline / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006321:Heart / Q000196:embryology; D008253:Macaca mulatta; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D015415:Biomarkers; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D017981:Receptors, Neurotransmitter; D017392:Thiobarbituric Acid Reactive Substances; D009538:Nicotine; D004247:DNA; D000262:Adenylyl Cyclases; D002794:Choline; D001205:Ascorbic Acid