Low dose effects of dichlorodiphenyltrichloroethane (DDT) on gene transcription and DNA methylation in the hypothalamus of young male rats: implication of hormesis-like effects.

Shutoh Y, Takeda M, Ohtsuka R, Haishima A, Yamaguchi S, Fujie H, Komatsu Y, Maita K, Harada T.

To verify the relationship between oxidative stress and DNA methylation in the young brain, dichlorodiphenyltrichloroethane (DDT) was administered by gavage to male young rats at doses of 0, 0.006, 0.06, 0.6, 6, and 60 mg/kg/day for a period of 4 weeks. The most conspicuous decrease in the lipid peroxidation level was observed in the 0.06 mg/kg/day group compared with controls. Microarray analysis of brain samples from the control and 0.06 mg/kg/day groups revealed that the expression of 40 genes was changed in the hypothalamus, whereas mRNA expression was unaltered in the hippocampus. This result suggests that the hypothalamus is more susceptible to low-level oxidative stress at the young period. We further examined this possibility by selecting 10 genes from the hypothalamic microarray data. RT-PCR analysis revealed that expression of 7 of these 10 genes was significantly changed in the 0.06 mg/kg/day group, compared with controls. Furthermore, RT-PCR analysis showed that mRNA expressions of Dnmt1, Hsp90 and Hsp70 in the hypothalamus were significantly lower in the 0.06 mg/kg/day group than in controls. Methylated DNA-PCR analysis in the hypothalamus revealed that 6 CpG islands were significantly hypomethylated compared with controls. Thus, we speculate that the DNA methylation machinery malfunctions under low levels of oxidative stress, thereby leading to incomplete methylation of specific gene regions. Our data indicate that a low level of oxidative stress appears to correlate positively with transcriptional down-regulation and hypomethylation, but the precise mechanisms underlying these processes are unclear.

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