Meyer Armando, Seidler Frederic J, Slotkin Theodore A
Centro de Estudos da Saúde do Trabalhador e Ecologia Humana, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Environ Health Perspect. 2004 Feb;112(2):170-8. doi: 10.1289/ehp.6690.
The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn2+); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.
毒死蜱(CPF)及相关杀虫剂对胎儿和新生儿的神经毒性是一个主要问题。CPF的发育影响涉及胆碱酯酶抑制之外的机制,特别是非神经靶点共有的细胞信号传导事件。在本研究中,我们评估了大鼠在不同发育窗口[孕期第(GD)9 - 12天或17 - 20天,出生后第(PN)1 - 4天或11 - 14天]暴露于CPF对心脏和肝脏腺苷酸环化酶(AC)信号级联的即时和长期影响。除了基础AC活性外,我们评估了对直接AC刺激剂(福斯高林、Mn2 +);对通过特定膜受体激活信号传导的异丙肾上腺素和胰高血糖素;以及对激活将受体与AC偶联的G蛋白的氟化钠的反应。当CPF剂量低于全身毒性阈值时,对AC几乎没有明显的即时影响。然而,在GD9 - 12、GD17 - 20或PN1 - 4暴露于CPF会引发成年期(PN60)出现的性别选择性影响,而后期暴露(PN11 - 14)引发的影响较小且无统计学意义,表明易损窗口关闭。大多数影响是异源的,涉及受体下游的信号元件,因此由多种输入共享;叠加在这种基本模式上,受体介导的反应也有选择性改变。这些结果表明,CPF的发育毒性超出了神经系统,包括对心脏和肝脏稳态至关重要的细胞信号级联。未来的工作需要解决这些影响对CPF暴露结束很久后可能出现的心血管和代谢紊乱的潜在影响。