| Developmental Exposure to Chlorpyrifos Elicits Sex-Selective Alterations of Serotonergic Synaptic Function in Adulthood: Critical Periods and Regional Selectivity for Effects on the Serotonin Transporter, Receptor Subtypes, and Cell Signaling Justin E. Aldridge, Frederic J. Seidler, and Theodore A. Slotkin Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA Abstract
During brain development, serotonin (5HT) provides essential neurotrophic signals, and in earlier work, we found that developmental exposure to chlorpyrifos (CPF) elicits short-term changes in 5HT systems. In the present study, we evaluated the effects in adulthood after CPF exposures from the neural tube stage [gestational days (GD) 9-12] and the late gestational period (GD17-20) through postnatal neuronal differentiation and synaptogenesis [postnatal days (PN) 1-4 and 11-14], using treatments below the threshold for systemic toxicity. With exposure on GD9-12, CPF elicited global elevations in 5HT1A and 5HT2 receptors and in the 5HT presynaptic transporter. The GD17-20 treatment elicited larger effects that displayed selectivity for regions with 5HT nerve terminals and that were preferential for males. Although similar receptor up-regulation was seen after PN1-4 exposure, the effects were larger in regions with 5HT cell bodies ; in addition, the presynaptic transporter was down-regulated in the nerve terminal zones of females. The PN11-14 exposure had much smaller effects on receptors but still elicited transporter suppression with the same regional and sex selectivity. Although CPF exposure on GD17-20, PN1-4, or PN11-14 altered the ability of 5HT to modulate adenylyl cyclase, this change did not correspond with the effects on 5HT receptors, suggesting an additional set of effects on proteins that transduce the 5HT signal. Our results indicate that CPF elicits long-lasting changes in 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction after exposure in discrete developmental windows that range from the neural tube stage through synaptogenesis. These effects are likely to contribute to neurobehavioral teratology of CPF. Key words: adenylyl cyclase, brain development, chlorpyrifos, organophosphate insecticides, serotonin receptors, serotonin transporter, sex-selective effects. Environ Health Perspect 112:148-155 (2004) . doi:10.1289/ehp.6713 available via http://dx.doi.org/ [Online 4 November 2003]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu We thank I. Thillai for technical assistance. This work was supported by National Institutes of Health grants ES10387 and ES10356 and by the Conselho Nacional de Pesquisa--CNPq/Brazil. The authors declare they have no competing financial interests. Received 28 August 2003 ; accepted 4 November 2003.
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