Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Brain Res Bull. 2014 Jan;100:44-54. doi: 10.1016/j.brainresbull.2013.10.014. Epub 2013 Nov 23.
This study explores how glucocorticoids sensitize the developing brain to the organophosphate pesticide, chlorpyrifos. Pregnant rats received a standard therapeutic dose (0.2mg/kg) of dexamethasone on gestational days 17-19; pups were given subtoxic doses of chlorpyrifos on postnatal days 1-4 (1mg/kg, <10% cholinesterase inhibition). We evaluated serotonin (5HT) synaptic function from postnatal day 30 to day 150, assessing the expression of 5HT receptors and the 5HT transporter, along with 5HT turnover (index of presynaptic impulse activity) in brain regions encompassing all the 5HT projections and cell bodies. These parameters are known targets for neurodevelopmental effects of dexamethasone and chlorpyrifos individually. In males, chlorpyrifos evoked overall elevations in the expression of 5HT synaptic proteins, with a progressive increase from adolescence to adulthood; this effect was attenuated by prenatal dexamethasone treatment. The chlorpyrifos-induced upregulation was preceded by deficits in 5HT turnover, indicating that the receptor upregulation was an adaptive response to deficient presynaptic activity. Turnover deficiencies were magnified by dexamethasone pretreatment, worsening the functional impairment caused by chlorpyrifos. In females, chlorpyrifos-induced receptor changes reflected relative sparing of adverse effects compared to males. Nevertheless, prenatal dexamethasone still worsened the 5HT turnover deficits and reduced 5HT receptor expression in females, demonstrating the same adverse interaction. Glucocorticoids are used in 10% of U.S. pregnancies, and are also elevated in maternal stress; accordingly, our results indicate that this group represents a large subpopulation that may have heightened vulnerability to developmental neurotoxicants such as the organophosphates.
本研究探讨了糖皮质激素如何使发育中的大脑对有机磷农药毒死蜱敏感。妊娠大鼠在妊娠第 17-19 天接受了标准治疗剂量（0.2mg/kg）的地塞米松；幼仔在产后第 1-4 天接受了亚毒性剂量的毒死蜱（1mg/kg，<10%胆碱酯酶抑制）。我们从产后第 30 天到第 150 天评估了 5-羟色胺（5HT）突触功能，评估了 5HT 受体和 5HT 转运体的表达，以及脑区的 5HT 周转率（突触前冲动活动的指标），这些脑区包含所有 5HT 投射和细胞体。这些参数是地塞米松和毒死蜱单独对神经发育作用的已知靶点。在雄性中，毒死蜱引起 5HT 突触蛋白表达的整体升高，从青春期到成年期呈逐渐增加；这种效应被产前地塞米松处理所减弱。5HT 周转率的缺陷先于氯吡硫磷诱导的上调，表明受体上调是对突触前活动不足的适应性反应。地塞米松预处理会放大 5HT 周转率的缺陷，从而加重氯吡硫磷引起的功能障碍。在雌性中，与雄性相比，氯吡硫磷诱导的受体变化反映了对不利影响的相对保护。然而，产前地塞米松预处理仍会加重雌性 5HT 周转率缺陷，并降低 5HT 受体表达，表明存在相同的不利相互作用。糖皮质激素在美国 10%的妊娠中使用，并且在母体应激中也会升高；因此，我们的结果表明，这一人群代表了一个很大的亚人群，他们可能对有机磷等发育神经毒物具有更高的易感性。
