Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum.
Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum.
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DOI：
10.1016/j.brainresbull.2010.01.003
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发表时间：
2010-04-05
影响因子：
3.8
通讯作者：
Slotkin TA
中科院分区：
文献类型：
--
作者：
Adigun AA;Wrench N;Levin ED;Seidler FJ;Slotkin TA
有机磷酸酯是发育神经毒剂，但最近的证据表明对新陈代谢和心血管功能有额外的不利影响。一种常见的机制是破坏通过环 AMP 介导的细胞信号传导，以神经体液受体、G 蛋白和腺苷酸环化酶 (AC) 本身为目标。早些时候，我们发现新生儿对硫磷会引起青春期肝脏 AC 通路的上调，但到了成年早期，这种影响就会减弱。然而，类似于糖尿病前期的代谢变化仍然存在。在这里，我们给新生大鼠（出生后 1-4 天，0.1 或 0.2 毫克/公斤/天）施用对硫磷，跨越了胆碱酯酶抑制的阈值，但我们将研究延长到了更晚的时候，即 5 个月龄。此外，我们还研究了连续 7 周摄入高脂肪饮食所带来的代谢挑战是否会加剧新生儿对硫磷的影响。单独的对硫磷可增加 Gi 的表达或功能，从而减少 AC 对氟化物的反应。控制AC活性的受体也受到影响：骨骼肌中的β-肾上腺素能受体（βAR）增加，而心脏中的β-肾上腺素受体减少，后者还表现出抑制AC的m2-毒蕈碱乙酰胆碱受体升高。高脂肪饮食还诱导AC信号的变化，增强肝脏AC对胰高血糖素的反应，同时损害心脏对氟化物或毛喉素的反应，并抑制βAR和m2-毒蕈碱受体；小脑的唯一变化是 βAR 的减少。尽管新生儿对硫磷暴露与高脂肪饮食之间没有显着的相互作用，但它们对同一信号级联的汇聚效应表明，早期对硫磷暴露，无论是单独暴露还是与饮食因素相结合，都可能导致全球肥胖和糖尿病发病率的增加。
Organophosphates are developmental neurotoxicants but recent evidence points to additional adverse effects on metabolism and cardiovascular function. One common mechanism is disrupted cell signaling mediated through cyclic AMP, targeting neurohumoral receptors, G-proteins and adenylyl cyclase (AC) itself. Earlier, we showed that neonatal parathion evokes later upregulation of the hepatic AC pathway in adolescence but that the effect wanes by young adulthood; nevertheless metabolic changes resembling prediabetes persist. Here, we administered parathion to neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day), straddling the threshold for cholinesterase inhibition, but we extended the studies to much later, 5 months of age. In addition, we investigated whether metabolic challenge imposed by consuming a high-fat diet for 7 weeks would exacerbate neonatal parathion’s effects. Parathion alone increased the expression or function of Gi, thus reducing AC responses to fluoride. Receptors controlling AC activity were also affected: β-adrenergic receptors (βARs) in skeletal muscle were increased, whereas those in the heart were decreased, and the latter also showed an elevation of m2-muscarinic acetylcholine receptors, which inhibit AC. The high-fat diet also induced changes in AC signaling, enhancing the hepatic AC response to glucagon while impairing the cardiac response to fluoride or forskolin, and suppressing βARs and m2-muscarinic receptors; the only change in the cerebellum was a decrease in βARs. Although there were no significant interactions between neonatal parathion exposure and a high-fat diet, their convergent effects on the same signaling cascade indicate that early OP exposure, separately or combination with dietary factors, may contribute to the worldwide increase in the incidence of obesity and diabetes.
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影响因子：
3.8
作者：
Lassiter, T. Leon;Ryde, Ian T.;Slotkin, Theodore A.
通讯作者：
Slotkin, Theodore A.
年轻墨西哥裔美国儿童的有机磷酸农药暴露和神经发育。
影响因子：
10.4
作者：
Eskenazi, Brenda;Marks, Amy R.;Bradman, Asa;Harley, Kim;Barr, Dana B.;Johnson, Caroline;Morga, Norma;Jewell, Nicholas A.
通讯作者：
Jewell, Nicholas A.
影响因子：
10.4
作者：
Gurunathan, S;Robson, M;Lioy, PJ
通讯作者：
Lioy, PJ
有机磷酸盐杀虫剂的比较发育神经毒性：对脑发育的影响与全身毒性分离。
影响因子：
10.4
作者：
Slotkin, Theodore A;Levin, Edward D;Seidler, Frederic J
通讯作者：
Seidler, Frederic J
影响因子：
10.4
作者：
Lassiter, T. Leon;Ryde, Ian T.;MacKillop, Emiko A.;Brown, Kathleen K.;Levin, Edward D.;Seidler, Frederic J.;Slotkin, Theodore A.
通讯作者：
Slotkin, Theodore A.