Department of Pharmacology and Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res Bull. 2011 May 30;85(3-4):225-30. doi: 10.1016/j.brainresbull.2011.03.021. Epub 2011 Mar 29.
Early-life exposure to organophosphate pesticides leads to subsequent hyperresponsiveness of β-adrenergic receptor-mediated cell signaling that regulates hepatic gluconeogenesis, culminating in metabolic abnormalities resembling prediabetes. In the current study, we evaluated the effects of chlorpyrifos or parathion on presynaptic sympathetic innervation to determine whether the postsynaptic signaling effects are accompanied by defects in neuronal input. We administered either chlorpyrifos or parathion to newborn rats using exposure paradigms known to elicit the later metabolic changes but found no alterations in either hepatic or cardiac norepinephrine levels in adolescence or adulthood. However, shifting chlorpyrifos exposure to the prenatal period did evoke changes: exposure early in gestation produced subsequent elevations in norepinephrine, whereas later gestational exposure produced significant deficits. We also distinguished the organophosphate effects from those of the glucocorticoid, dexamethasone, a known endocrine disruptor that leads to later-life metabolic and cardiovascular disruption. Postnatal exposure to dexamethasone elicited deficits in peripheral norepinephrine levels but prenatal exposure did not. Our results indicate that early-life exposure to organophosphates leads to subsequent abnormalities of peripheral sympathetic innervation through mechanisms entirely distinct from those of glucocorticoids, ruling out the possibility that the organophosphate effects are secondary to stress or disruption of the HPA axis. Further, the effects on innervation were separable from those on postsynaptic signaling, differing in critical period as well as tissue- and sex-selectivity. Organophosphate targeting of both presynaptic and postsynaptic β-adrenergic sites, each with different critical periods of vulnerability, thus sets the stage for compounding of hepatic and cardiac functional abnormalities.
早期接触有机磷农药会导致随后β-肾上腺素能受体介导的细胞信号转导过度敏感，从而调节肝糖异生，最终导致类似于糖尿病前期的代谢异常。在本研究中，我们评估了氯吡硫磷或对硫磷对交感神经节前支配的影响，以确定突触后信号转导效应是否伴有神经元输入缺陷。我们使用已知会引起后期代谢变化的暴露范式向新生大鼠给予氯吡硫磷或对硫磷，但在青春期或成年期均未发现肝或心脏去甲肾上腺素水平发生变化。然而，将氯吡硫磷的暴露转移到产前阶段确实会引起变化：妊娠早期暴露会导致随后去甲肾上腺素水平升高，而晚期妊娠暴露会导致明显的缺陷。我们还将有机磷的作用与糖皮质激素地塞米松的作用区分开来，地塞米松是一种已知的内分泌干扰物，会导致后期生活中的代谢和心血管紊乱。产后暴露于地塞米松会引起外周去甲肾上腺素水平降低，但产前暴露则不会。我们的结果表明，早期接触有机磷会通过与糖皮质激素完全不同的机制导致外周交感神经支配的后续异常，排除了有机磷作用是继发于应激或 HPA 轴破坏的可能性。此外，对神经支配的影响与突触后信号转导的影响不同，在关键期以及组织和性别选择性方面存在差异。有机磷对突触前和突触后β-肾上腺素能部位的靶向作用，每个部位都有不同的脆弱关键期，从而为肝和心脏功能异常的复合作用奠定了基础。
