Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity
Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity
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DOI：
10.1016/s0165-3806(00)00021-3
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发表时间：
2000-05-11
期刊：
影响因子：
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通讯作者：
Slotkin, TA
中科院分区：
文献类型：
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作者：
Auman, JT;Seidler, FJ;Slotkin, TA
毒死蜱已被假设与受体和转导蛋白参与生产环磷酸腺苷，促进细胞复制和分化的不利影响。我们研究了新生儿毒死蜱暴露对肝脏腺苷酸环化酶（AC）活性的影响，因为肝脏积累了最高浓度的毒死蜱，并且是其活性代谢物毒死蜱oxon的生成场所。新生大鼠皮下注射毒死蜱1 mg/kg。在PN 1 -4。在PN 5，末次给药后24 h，通过对直接AC刺激剂Mn 2+的反应评估诱导AC催化活性。相反，AC激活依赖于酶与G-蛋白（毛喉素）的相互作用没有显示出任何增强，这表明G-蛋白功能的损害。这一结论得到了对氟化物的反应性受损的证实，氟化物直接激活G蛋白。此外，AC对激素信号的反应以受体选择性方式改变，对胰高血糖素的反应增强，但对β-肾上腺素受体激动剂异丙肾上腺素的反应不增强。毒死蜱对AC信号传导的影响显示了脆弱性的关键发育期，因为对老年大鼠（PN 11 -14）的治疗未能引起AC的实质性诱导或G蛋白信号传导的干扰，尽管它仍然增强了胰高血糖素反应。在所有情况下，毒死蜱的影响在停止治疗的几天内消失。这些结果与同样的毒死蜱处理后大脑中AC信号的延迟恶化形成对比。毒死蜱对AC级联效应的时间和器官选择性表明，膜信号传导的中断是对细胞发育的选择性效应的结果，而不是代表毒死蜱和信号蛋白之间的直接相互作用。(C)2000 Elsevier Science BN。All rights reserved.
Chlorpyrifos has been hypothesized to interact with receptors and transduction proteins involved in the production of cyclic AMP, contributing to adverse effects on cell replication and differentiation. We studied the effects of neonatal chlorpyrifos exposure on hepatic adenylyl cyclase (AC) activity, as the liver accumulates the highest concentrations of chlorpyrifos and is the site for generation of its active metabolite, chlorpyrifos oxon. Newborn rats were given 1 mg/kg of chlorpyrifos s.c. on PN1-4. On PN5, 24 h after the last dose, AC catalytic activity was induced as assessed by the response to the direct AC stiimulant, Mn2+. In contrast, AC activation dependent upon interaction of the enzyme with G-proteins (forskolin) did not show any enhancement, suggesting impairment of G-protein function. This conclusion was confirmed by impaired responsiveness to fluoride, which directly activates G-proteins. In addition, the response of AC to hormonal signals was altered in a receptor-selective manner with an enhanced response to glucagon but not to the beta-adrenoceptor agonist, isoproterenol. The effects of chlorpyrifos on AC signaling displayed a critical developmental period of vulnerability, as treatment of older rats (PN11-14) failed to cause substantial induction of AC or interference with G-protein signaling, although it did still enhance the glucagon response. In all cases, the effects of chlorpyrifos disappeared within a few days of discontinuing treatment. These results stand in contrast to the delayed deterioration of AC signaling seen in the brain after the same chlorpyrifos treatment. The temporal and organ selectivity of chlorpyrifos' effects on the AC cascade suggest that disruption of membrane signaling occurs consequent to selective effects on cell development, rather than representing a direct interaction between chlorpyrifos and signaling proteins. (C) 2000 Elsevier Science BN. All rights reserved.