Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation
Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation
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DOI：
10.1016/s0006-8993(99)02357-4
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发表时间：
2000-02-28
期刊：
影响因子：
2.9
通讯作者：
Slotkin, TA
中科院分区：
文献类型：
--
作者：
Crumpton, TL;Seidler, FJ;Slotkin, TA
毒死蜱是一种广泛使用的有机磷杀虫剂，被怀疑是一种发育神经毒素。虽然毒死蜱通过抑制胆碱酯酶发挥一些作用，但最近的研究表明，毒死蜱对发育中的细胞有其他直接作用。我们通过体外和体内模型评估了毒死蜱对参与细胞复制和分化的核转录因子的影响。在毒死蜱存在和不存在的情况下，用标记的AP-1和Spl转录因子的一致寡核苷酸孵育HeLa核蛋白提取物。在先前显示影响细胞发育的浓度下，毒死蜱降低了AP-1，但没有降低Spl dna结合活性。接下来，毒死蜱与PC12细胞孵育，在细胞复制期间或与NGF开始分化后。毒死蜱对转录因子的表达产生了阶段性干扰：Spl在复制和分化细胞中减少，而AP-1仅在分化过程中受到影响。最后，在出生后1-4天或11-14天给予新生大鼠明显亚毒性剂量的毒死蜱，并评估其对前脑（早期发育的胆碱能靶区）和小脑（后期发育的胆碱能神经支配较差的区域）的影响。同样，毒死蜱引起了转录因子表达和结合活性的阶段特异性变化，在活跃的神经发生期间对Spl的影响更大，在分化期间对AP-1的影响更大。这种变化出现在前脑和小脑，并且是性别特异性的。这些结果表明，毒死蜱干扰大脑发育，部分原因是参与细胞复制和分化基本机制的转录因子活性的多重改变。毒死蜱对大脑发育的非胆碱能作用是大脑发育所特有的，因此需要检查除胆碱酯酶抑制外的其他终点。(C) 2000 Elsevier Science B.V.版权所有
Chlorpyrifos is a widely used organophosphate insecticide that is a suspected developmental neurotoxin. Although chlorpyrifos exerts some effects through cholinesterase inhibition, recent studies suggest additional, direct actions on developing cells. We assessed the effects of chlorpyrifos on nuclear transcription factors involved in cell replication and differentiation using in vitro and in vivo models. HeLa nuclear protein extracts were incubated with the labeled consensus oligonucleotides for AP-1 and Spl transcription factors in the presence and absence of chlorpyrifos. In concentrations previously shown to affect cell development, chlorpyrifos reduced AP-1, but not Spl DNA-binding activity. Next, chlorpyrifos was incubated with PC12 cells either during cell replication or after initiation of differentiation with NGF. Chlorpyrifos evoked stage-specific interference with the expression of the transcription factors: Spl was reduced in replicating and differentiating cells, whereas AP-1 was affected only during differentiation. Finally, neonatal rats were given apparently subtoxic doses of chlorpyrifos either on postnatal days 1-4 or 11-14 and the effects were evaluated in the forebrain (an early-developing, cholinergic target region) and cerebellum (late-developing region, poor in cholinergic innervation). Again, chlorpyrifos evoked stage-specific changes in transcription factor expression and binding activity, with greater effects on Spl during active neurogenesis, and effects on AP-1 during differentiation. The changes were present in both forebrain and cerebellum and were gender-specific. These results indicate that chlorpyrifos interferes with brain development, in part by multiple alterations in the activity of transcription factors involved in the basic machinery of cell replication and differentiation Noncholinergic actions of chlorpyrifos that are unique to brain development reinforce the need to examine endpoints other than cholinesterase inhibition. (C) 2000 Elsevier Science B.V. All rights reserved.