| Critical Periods for Chlorpyrifos-Induced Developmental Neurotoxicity: Alterations in Adenylyl Cyclase Signaling in Adult Rat Brain Regions after Gestational or Neonatal Exposure Armando Meyer,1 Frederic J. Seidler,2 Justin E. Aldridge,2 Charlotte A. Tate,2 Mandy M. Cousins,2 and Theodore A. Slotkin2 1Centro de Estudos da Saúde do Trabalhador e Ecologia Humana, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; 2Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA Abstract
Developmental exposure to chlorpyrifos (CPF) alters the function of a wide variety of neural systems. In the present study we evaluated the effects in adulthood of CPF exposure of rats during different developmental windows, using the adenylyl cyclase (AC) signaling cascade, which mediates the cellular responses to numerous neurotransmitters. Animals were exposed on gestational days (GD) 9-12 or 17-20 or on postnatal days (PN) 1-4 or 11-14 and assessed at PN60. In addition to basal AC activity, we evaluated the responses to direct AC stimulants (forskolin, Mn2+) and to isoproterenol, which activates signaling through ß-adrenoceptors coupled to stimulatory G-proteins. CPF exposure in any of the four periods elicited significant changes in AC signaling in a wide variety of brain regions in adulthood. In general, GD9-12 was the least sensitive stage, requiring doses above the threshold for impaired maternal weight gain, whereas effects were obtained at subtoxic doses for all other regimens. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus shared by multiple stimulants ; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses, in G-protein function, and in AC expression and subtypes. Exposures conducted at GD17-20 and later all produced sex-selective alterations. These results suggest that developmental exposure to CPF elicits long-lasting alterations in cell-signaling cascades that are shared by multiple neurotransmitter and hormonal inputs ; the resultant abnormalities of synaptic communication are thus likely to occur in widespread neural circuits and their corresponding behaviors. Key words: adenylyl cyclase, ß-adrenoceptor, brain development, chlorpyrifos, organophosphate insecticides. Environ Health Perspect 112:295-301 (2004) . doi:10.1289/ehp.6755 available via http://dx.doi.org/ doi:10.1289/ehp.6755 available via http://dx.doi.org/ [Online 24 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 This work was supported by grants ES10387 and ES10356 from the U.S. Public Health Service and by Conselho Nacional de Pesquisa - CNPq/Brazil. The authors declare they have no competing financial interests. Received 22 September 2003 ; accepted 24 November 2003.
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