| Perinatal Environmental Tobacco Smoke Exposure in Rhesus Monkeys: Critical Periods and Regional Selectivity for Effects on Brain Cell Development and Lipid Peroxidation Theodore A. Slotkin,1 Kent E. Pinkerton,2 and Frederic J. Seidler1 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA; 2Center for Health and the Environment, and California National Primate Research Center, University of California, Davis, California, USA Abstract
Perinatal environmental tobacco smoke (ETS) exposure in humans elicits neurobehavioral deficits. We exposed rhesus monkeys to ETS during gestation and through 13 months postnatally, or postnatally only (6-13 months) . At the conclusion of exposure, we examined cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation. For perinatal ETS, two archetypal patterns were seen in the various regions, one characterized by cell loss (reduced DNA concentration) and corresponding increases in cell size (increased protein/DNA ratio) , and a second pattern suggesting replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/DNA ratio) . The membrane/total protein ratio, a biomarker of neurite formation, also indicated potential damage to neuronal projections, accompanied by reactive sprouting. When ETS exposure was restricted to the postnatal period, the effects were similar in regional selectivity, direction, and magnitude. These patterns resemble the effects of prenatal nicotine exposure in rodent and primate models. Surprisingly, perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not. The heart, a tissue that, like the brain, has high oxygen demand, displayed a similar but earlier decrease (2-3 months) in lipid peroxidation in the perinatal exposure model, whereas values were reduced at 13 months with the postnatal exposure paradigm. Our results provide a mechanistic connection between perinatal ETS exposure and neurobehavioral anomalies, reinforce the role of nicotine in these effects, and buttress the importance of restricting or eliminating ETS exposure in young children. Key words: β-adrenergic receptor, brain development, environmental tobacco smoke, heart development, lipid peroxidation, muscarinic acetylcholine receptor, nicotine. Environ Health Perspect 114:34-39 (2006) . doi:10.1289/ehp.8286 available via http://dx.doi.org/ [Online 7 September 2005]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu. We thank M.M. Cousins, C.A. Oliver, and C.A. Tate for technical assistance. Research was supported by grants from the Philip Morris External Research Program and the National Institutes of Health (ES011634, ES05707, and RR00169) . The authors declare they have no competing financial interests. Received 5 May 2005 ; accepted 7 September 2005.
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