Effects of Mixtures of Polychlorinated Biphenyls, Methylmercury, and Organochlorine Pesticides on Hepatic DNA Methylation in Prepubertal Female Sprague-Dawley Rats
Effects of Mixtures of Polychlorinated Biphenyls, Methylmercury, and Organochlorine Pesticides on Hepatic DNA Methylation in Prepubertal Female Sprague-Dawley Rats
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DOI：
10.1177/1091581809337918
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发表时间：
2009-07-01
影响因子：
2.2
通讯作者：
Bowers, Wayne J.
中科院分区：
文献类型：
--
作者：
Desaulniers, Daniel;Xiao, Gong-hua;Bowers, Wayne J.
DNA甲基化是调节基因表达、染色体结构和稳定性的表观遗传机制之一。我们的目的是确定DNA甲基化系统是否可以成为子宫内和出生后暴露于人类血液污染物的目标。从妊娠第1天到产后第21天，每天给孕鼠施用两种剂量水平的有机氯农药（OCP; 0.019或1.9 mg/kg/天），氯化甲基汞（甲基汞; 0.02或2毫克/千克/天）、多氯联苯（多氯联苯; 0.011或1.1毫克/公斤/天），或混合物（混合; 0.05或5毫克/公斤/天），包括所有3组化学品。在出生后第29天采集每窝1只雌性后代的肝脏。肝脏分析表明，DNA甲基转移酶（DNMT）-1，3a和-3b的mRNA丰度显着减少的高剂量的PCB，高剂量的甲基汞也降低了DNMT-1，和-3b的mRNA水平，但OCP没有显着的影响与对照组相比。高剂量的PCB和Mix降低了通用甲基供体S-腺苷甲硫氨酸的丰度，Mix还降低了整体基因组DNA甲基化（5-甲基-脱氧胞苷/5-甲基-脱氧胞苷+脱氧胞苷）。后者与焦磷酸测序甲基化分析一致，显示高剂量组（OCP除外）普遍降低了抑癌基因p16（INK 4a）启动子CpG位点（-63至-29位）的甲基化。总的来说，这些肝脏结果表明，DNA甲基化系统可能会受到高剂量血液污染物的影响，OCP是所研究混合物中效力最低的化学基团。
DNA methylation is one of the epigenetic mechanisms that regulates gene expression, chromosome structure, and stability. Our objective was to determine whether the DNA methylation system could be a target following in utero and postnatal exposure to human blood contaminants. Pregnant rats were dosed daily from gestation day 1 until postnatal day 21 with 2 dose levels of either organochlorine pesticides (OCP; 0.019 or 1.9 mg/kg/day), methylmercury chloride (MeHg; 0.02 or 2 mg/kg/day), polychlorinated biphenyls (PCBs; 0.011 or 1.1 mg/kg/day), or a mixture (Mix; 0.05, or 5 mg/kg/day) including all 3 groups of chemicals. Livers from 1 female offspring per litter were collected at postnatal day 29. Hepatic analysis revealed that the mRNA abundance for DNA methyltransferase (DNMT)-1, -3a, and -3b were significantly reduced by the high dose of PCB, that the high dose of MeHg also reduced mRNA levels for DNMT-1, and -3b, but that OCP had no significant effects compared with control. The high dose of PCB and Mix reduced the abundance of the universal methyl donor S-adenosylmethionine, and Mix also reduced global genome DNA methylation (5-methyl-deoxycytidine/5-methyl-deoxycytidine + deoxycytidine). The latter is consistent with pyrosequencing methylation analysis, revealing that the high-dose groups (except OCP) generally decreased the methylation of CpG sites (position -63 to -29) in the promoter of the tumor suppressor gene p16(INK4a). Overall, these hepatic results suggest that the DNA methylation system can be affected by exposure to high doses of blood contaminants, and that OCP is the least potent chemical group from the investigated mixtures.