Abdel-Rahman Ali, Dechkovskaia Anjelika M, Mehta-Simmons Heena, Sutton Jazmine M, Guan Xiangrong, Khan Wasiuddin A, Abou-Donia Mohamed B
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Arch Toxicol. 2004 Aug;78(8):467-76. doi: 10.1007/s00204-004-0560-5. Epub 2004 Mar 26.
We previously showed that maternal exposure to nicotine, alone or in combination with chlorpyrifos, caused an increase in glial fibrillary acidic protein (GFAP) immunostaining in the CA1 subfield of hippocampus and cerebellum in postnatal day (PND) 30 offspring. In the present study, PND 60 offspring were evaluated for histopathological and cholinergic effects following maternal exposure to nicotine and chlorpyrifos, alone and in combination. Timed-pregnant Sprague-Dawley rats (300-350 g) were treated daily with nicotine (1 mg/kg, s.c., in normal saline) or chlorpyrifos (0.1 mg/kg, dermal, in ethanol) or a combination of nicotine and chlorpyrifos from gestational days (GD) 4 to 20. Control animals were treated with saline and ethanol. On PND 60, the offspring were evaluated for cholinergic changes and pathological effects. Plasma butyrylcholinesterase (BChE) activity in the female offspring from chlorpyrifos treated mothers showed a significant increase (approximately 183% of control). Male offspring from mothers treated with either chlorpyrifos or nicotine alone showed a significant increase in the acetylcholinesterase (AChE) activity in the brainstem while female offspring from mothers treated with either nicotine or a combination of nicotine and chlorpyrifos showed a significant increase (approximately 134 and 126% of control, respectively) in AChE activity in the brainstem. No significant changes were observed in the ligand binding densities for alpha4beta2 and alpha7 nicotinic acetylcholine receptors in the cortex. Histopathological evaluation using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum of the offspring from nicotine treated mothers. An increase in GFAP immunostaining in cerebellar white matter was observed in the offspring from the mothers treated with nicotine. These results suggest that maternal exposure to real-life levels of nicotine and/or chlorpyrifos causes differential regulation of brainstem AChE activity. Also, nicotine caused a decrease in the surviving neurons and an increased expression of GFAP in cerebellar white matter of the offspring on PND 60. These changes can lead to long-term neurological adverse health effects later in life.
我们之前的研究表明，母体暴露于尼古丁，单独或与毒死蜱联合暴露，会导致出生后第30天（PND 30）子代海马体和小脑CA1亚区的胶质纤维酸性蛋白（GFAP）免疫染色增加。在本研究中，对PND 60的子代进行了组织病理学和胆碱能效应评估，这些子代的母体曾单独或联合暴露于尼古丁和毒死蜱。将定时受孕（妊娠300 - 350克）的斯普拉格 - 道利大鼠从妊娠第4天至第20天每天用尼古丁（1毫克/千克，皮下注射，溶于生理盐水）或毒死蜱（0.1毫克/千克，经皮涂抹，溶于乙醇）或尼古丁与毒死蜱的组合进行处理。对照动物用生理盐水和乙醇处理。在PND 60时，评估子代的胆碱能变化和病理效应。来自毒死蜱处理组母体的雌性子代血浆丁酰胆碱酯酶（BChE）活性显著增加（约为对照组的183%）。单独用毒死蜱或尼古丁处理的母体所生的雄性子代脑干中的乙酰胆碱酯酶（AChE）活性显著增加，而用尼古丁或尼古丁与毒死蜱组合处理的母体所生的雌性子代脑干中的AChE活性显著增加（分别约为对照组的13^{4}%和126%）。在皮质中，α4β2和α7烟碱型乙酰胆碱受体的配体结合密度未观察到显著变化。使用甲酚紫染色的组织病理学评估显示，来自尼古丁处理组母体的子代小脑中存活的浦肯野神经元显著减少。在用尼古丁处理的母体所生的子代小脑中，观察到小脑白质中GFAP免疫染色增加。这些结果表明，母体暴露于实际生活水平的尼古丁和/或毒死蜱会导致脑干AChE活性的差异调节。此外，尼古丁导致PND 60子代小脑中存活神经元数量减少以及小脑白质中GFAP表达增加。这些变化可能会在以后的生活中导致长期的神经健康不良影响。
