title: Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.
abstract: Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.
authors.affiliation: *Department of Pharmacology and Cancer Biology; and t.slotkin@duke.edu.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.affiliation: *Department of Pharmacology and Cancer Biology; and.
authors.forename: Samantha
authors.initials: S
authors.lastname: Skavicus
authors.affiliation: *Department of Pharmacology and Cancer Biology; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Card
authors.affiliation: *Department of Pharmacology and Cancer Biology; and.
authors.forename: Ashley
authors.initials: A
authors.lastname: Stadler
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.affiliation: *Department of Pharmacology and Cancer Biology; and.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D005260:Female; D008297:Male; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D009538:Nicotine / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects; D012701:Serotonin; D012727:Sex Characteristics; D012906:Smoke / Q000009:adverse effects*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D062789:Tobacco Products
chemical_list: D011985:Receptors, Serotonin; D012906:Smoke; D012701:Serotonin; D009538:Nicotine
keywords: acetylcholine systems; developmental neurotoxicity; nicotine; serotonin systems: tobacco smoke