Developmental Neurotoxicity Elicited by Gestational Exposure to Chlorpyrifos: When Is Adenylyl Cyclase a Target?

NEUROTOXICOLOGY; CHLORPYRIFOS; CHOLINESTERASE-inhibiting insecticides; ADENYLATE cyclase; CYCLIC adenylic acid; PREGNANCY; DEVELOPMENTAL disabilities

The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms over and above cholinesterase inhibition. In the present study, we evaluated the effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling cascade, which regulates the production of cyclic AMP, a major controller of cell replication and differentiation. In addition to basal AC activity, we assessed the AC response to direct enzymatic stimulants [forskolin, manganese (Mn[sup 2+])]; the response to isoproterenol, which activates signaling through β-adrenoceptors (βARs); and the concentration of βAR binding sites. CPF administered to pregnant rats on gestational days (GD) 9-12 elicited little or no change in any components of AC activity or βARs. However, shifting the treatment window to GD 17-20 produced regionally selective augmentation of AC activity. In the brainstem, the response to forskolin or Mn[sup 2+]. was markedly stimulated by doses at or below the threshold for observable toxicity of CPF or for inhibition of fetal brain cholinesterase, whereas comparable effects were seen in the forebrain only at higher doses. In addition, low doses of CPF reduced βAR binding without impairing receptor-mediated stimulation of AC. These results indicate that signal transduction through the AC cascade is a target for CPF during a discrete developmental period in late gestation, an effect that is likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity. [ABSTRACT FROM AUTHOR]

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