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Effects of Mixtures of Polychlorinated Biphenyls, Methylmercury, and Organochlorine Pesticides on Hepatic DNA Methylation in Prepubertal Female Sprague-Dawley Rats

From the Hazard Identification Division, Health Canada, Healthy Environments and Consumer Safety Branch, Environmental Health Science and Research Bureau, Ottawa, Ontario, Canada; and Exposure and Biomonitoring Division, Health Canada, Healthy Environments and Consumer Safety Branch, Environmental Health Science and Research Bureau, Ottawa, Ontario, Canada.

Correspondence: Please address correspondence to Daniel Desaulniers, PhD, Health Canada, Healthy Environments and Consumer Safety Branch, Environmental Health Science and Research Bureau, Hazard Identification Division, AL: 0803D Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0K9; e-mail:Daniel_Desaulniers{at}hc-sc.gc.ca.

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.

Key Words: DNA methylation • rat • mixture • methylmercury • polychlorinated biphenyls • organochlorine pesticides

International Journal of Toxicology, Vol. 28, No. 4, 294-307 (2009)
DOI: 10.1177/1091581809337918


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