Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity

Chlorpyrifos has been hypothesized to interact with receptors and transduct ion proteins involved in the production of cyclic AMP, contributing to adve rse effects on cell replication and differentiation. We studied the effects of neonatal chlorpyrifos exposure on hepatic adenylyl cyclase (AC) activit y, as the liver accumulates the highest concentrations of chlorpyrifos and is the site for generation of its active metabolite, chlorpyrifos oxon. New born rats were given 1 mg/kg of chlorpyrifos s.c. on PN1-4. On PN5, 24 h af ter the last dose, AC catalytic activity was induced as assessed by the res ponse to the direct AC stiimulant, Mn2+. In contrast, AC activation depende nt upon interaction of the enzyme with G-proteins (forskolin) did not show any enhancement, suggesting impairment of G-protein function. This conclusi on was confirmed by impaired responsiveness to fluoride, which directly act ivates G-proteins. In addition, the response of AC to hormonal signals was altered in a receptor-selective manner with an enhanced response to glucago n but not to the beta-adrenoceptor agonist, isoproterenol. The effects of c hlorpyrifos on AC signaling displayed a critical developmental period of vu lnerability, as treatment of older rats (PN11-14) failed to cause substanti al induction of AC or interference with G-protein signaling, although it di d still enhance the glucagon response. In all cases, the effects of chlorpy rifos disappeared within a few days of discontinuing treatment. These resul ts stand in contrast to the delayed deterioration of AC signaling seen in t he brain after the same chlorpyrifos treatment. The temporal and organ sele ctivity of chlorpyrifos' effects on the AC cascade suggest that disruption of membrane signaling occurs consequent to selective effects on cell develo pment, rather than representing a direct interaction between chlorpyrifos a nd signaling proteins. (C) 2000 Elsevier Science BN. All rights reserved.