McCallister Monique M, Maguire Mark, Ramesh Aramandla, Aimin Qiao, Liu Sheng, Khoshbouei Habibeh, Aschner Michael, Ebner Ford F, Hood Darryl B
Department of Neurobiology and Neurotoxicology, Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville, TN 37208, USA.
Neurotoxicology. 2008 Sep;29(5):846-54. doi: 10.1016/j.neuro.2008.07.008. Epub 2008 Aug 9.
Prenatal exposure to environmental contaminants, such as benzo(a)pyrene [B(a)P] has been shown to impair brain development. The overarching hypothesis of our work is that glutamate receptor subunit expression is crucial for cortical evoked responses and that prenatal B(a)P exposure modulates the temporal developmental expression of glutamatergic receptor subunits in the somatosensory cortex. To characterize prenatal B(a)P exposure on the development of cortical function, pregnant Long Evans rats were exposed to low-level B(a)P (300 microg/kg BW) by oral gavage on gestational days 14-17. At this exposure dose, there was no significant effect of B(a)P on (1) the number of pups born per litter, (2) the pre-weaning growth curves and (3) initial and final brain to body weight ratios. Control and B(a)P-exposed offspring were profiled for B(a)P metabolites in plasma and whole brain during the pre-weaning period. No detectable levels of metabolites were found in the control offspring. However, a time-dependent decrease in total metabolite concentration was observed in B(a)P-exposed offspring. On PND100-120, cerebrocortical mRNA expression was determined for the glutamatergic NMDA receptor subunit (NR2B) in control and B(a)P-exposed offspring. Neural activity was also recorded from neurons in primary somatic sensory (barrel) cortex. Semiquantitative PCR from B(a)P-exposed offspring revealed a significant 50% reduction in NR2B mRNA expression in B(a)P-exposed offspring relative to controls. Recordings from B(a)P-exposed offspring revealed that N-methyl-d-aspartate (NMDA) receptor-dependent neuronal activity in barrel cortex evoked by whisker stimulation was also significantly reduced (70%) as compared to controls. Analysis showed that the greatest deficit in cortical neuronal responses occurred in the shorter latency epochs from 5 to 20 ms post-stimulus. The results suggest that in utero exposure to benzo(a)pyrene results in diminished mRNA expression of the NMDA NR2B receptor subunit to result in late life deficits in cortical neuronal activity in the offspring. The findings from this study lead to a strong prediction that in utero exposure to benzo(a)pyrene at a time when synapses are first formed and adjusted in strength by activity in the sensory pathways will produce a strong negative effect on brain function in offspring progeny.
产前暴露于环境污染物，如苯并(a)芘[B(a)P]，已被证明会损害大脑发育。我们研究的总体假设是，谷氨酸受体亚基的表达对皮质诱发反应至关重要，并且产前暴露于B(a)P会调节躯体感觉皮质中谷氨酸能受体亚基的时间发育表达。为了表征产前暴露于B(a)P对皮质功能发育的影响，在妊娠第14 - 17天，通过口服灌胃法让怀孕的Long Evans大鼠暴露于低剂量的B(a)P（300微克/千克体重）。在这个暴露剂量下，B(a)P对以下方面没有显著影响：(1)每窝出生的幼崽数量；(2)断奶前的生长曲线；(3)初始和最终脑体重比。在断奶前阶段，对对照组和暴露于B(a)P的后代的血浆和全脑中的B(a)P代谢物进行了分析。在对照组后代中未检测到代谢物水平。然而，在暴露于B(a)P的后代中观察到总代谢物浓度随时间下降。在出生后第100 - 120天，测定了对照组和暴露于B(a)P的后代大脑皮质中谷氨酸能NMDA受体亚基（NR2B）的mRNA表达。还记录了初级躯体感觉（桶状）皮质中神经元的神经活动。对暴露于B(a)P的后代进行的半定量PCR显示，与对照组相比，暴露于B(a)P的后代中NR2B mRNA表达显著降低了50%。对暴露于B(a)P的后代的记录显示，与对照组相比，触须刺激诱发的桶状皮质中N - 甲基 - d - 天冬氨酸（NMDA）受体依赖性神经元活动也显著降低（70%）。分析表明，皮质神经元反应的最大缺陷出现在刺激后5至20毫秒的较短潜伏期时段。结果表明，子宫内暴露于苯并(a)芘会导致NMDA NR2B受体亚基的mRNA表达减少，从而导致后代后期皮质神经元活动出现缺陷。这项研究的结果有力地预测，在突触首次形成并通过感觉通路中的活动进行强度调整时，子宫内暴露于苯并(a)芘将对后代的脑功能产生强烈的负面影响。
