BACKGROUND Maternal exposure to environmental chemicals can cause adverse health effects in offspring. Mounting evidence supports that these effects are influenced, at least in part, by epigenetic modifications. It is unknown whether epigenetic changes in surrogate tissues such as the blood are reflective of similar changes in target tissues such as cortex or liver. OBJECTIVE We examined tissue- and sex-specific changes in DNA methylation (DNAm) associated with human-relevant lead (Pb) and di(2-ethylhexyl) phthalate (DEHP) exposure during perinatal development in cerebral cortex, blood, and liver. METHODS Female mice were exposed to human relevant doses of either Pb (32 ppm) via drinking water or DEHP (5mg/kg-day) via chow for 2 weeks prior to mating through offspring weaning. Whole genome bisulfite sequencing (WGBS) was utilized to examine DNAm changes in offspring cortex, blood, and liver at 5 months of age. Metilene and methylSig were used to identify differentially methylated regions (DMRs). Annotatr and ChIP-enrich were used for genomic annotations and gene set enrichment tests of DMRs, respectively. RESULTS The cortex contained the majority of DMRs associated with Pb (66%) and DEHP (57%) exposure. The cortex also contained the greatest degree of overlap in DMR signatures between sexes (n=13 and 8 DMRs with Pb and DEHP exposure, respectively) and exposure types (n=55 and 39 DMRs in males and females, respectively). In all tissues, detected DMRs were preferentially found at genomic regions associated with gene expression regulation (e.g., CpG islands and shores, 5' UTRs, promoters, and exons). An analysis of GO terms associated with DMR-containing genes identified imprinted genes to be impacted by both Pb and DEHP exposure. Of these, Gnas and Grb10 contained DMRs across tissues, sexes, and exposures, with some signatures replicated between target and surrogate tissues. DMRs were enriched in the imprinting control regions (ICRs) of Gnas and Grb10, and we again observed a replication of DMR signatures between blood and target tissues. Specifically, we observed hypermethylation of the Grb10 ICR in both blood and liver of Pb-exposed male animals. CONCLUSIONS These data provide preliminary evidence that imprinted genes may be viable candidates in the search for epigenetic biomarkers of toxicant exposure in target tissues. Additional research is needed on allele- and developmental stage-specific effects, as well as whether other imprinted genes provide additional examples of this relationship. https://doi.org/10.1289/EHP14074.

中文翻译：

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发育性铅和邻苯二甲酸盐暴露对成年小鼠血液、大脑和肝脏中 DNA 甲基化的影响：关注组织和性别的基因组印记。


背景 母亲接触环境化学物质会对后代的健康造成不利影响。越来越多的证据支持这些影响至少部分受到表观遗传修饰的影响。目前尚不清楚替代组织（如血液）的表观遗传变化是否反映了靶组织（如皮层或肝脏）的类似变化。目的 我们检查了大脑皮层、血液和肝脏围产期发育过程中与人类相关铅 （Pb） 和邻苯二甲酸二（2-乙基己基）酯 （DEHP） 暴露相关的 DNA 甲基化 （DNAm） 的组织特异性变化。方法 雌性小鼠在交配至后代断奶前通过 2 周通过饮水暴露于人类相关剂量的 Pb （32 ppm） 或通过食物暴露于 DEHP （5mg/kg-d） 2 周。全基因组亚硫酸氢盐测序 （WGBS） 用于检查 5 月龄后代皮层、血液和肝脏的 DNAm 变化。使用 Metilene 和 methylSig 鉴定差异甲基化区域 （DMR）。Annotatr 和 ChIP-enriched 分别用于 DMR 的基因组注释和基因集富集测试。结果 皮层包含大多数与 Pb （66%） 和 DEHP （57%） 暴露相关的 DMR。皮层在性别（分别为 pb 和 DEHP 暴露的 n=13 和 8 个 DMR）和暴露类型（男性和女性分别为 n=55 和 39 个 DMR）之间的 DMR 特征也包含最大程度的重叠。在所有组织中，检测到的 DMR 优先存在于与基因表达调控相关的基因组区域（例如，CpG 岛和海岸、5' UTR、启动子和外显子）。对与含 DMR 的基因相关的 GO 术语的分析确定了受 Pb 和 DEHP 暴露影响的印记基因。 其中，Gnas 和 Grb10 包含跨组织、性别和暴露的 DMR，一些特征在靶组织和替代组织之间复制。DMRs 在 Gnas 和 Grb10 的印记控制区 （ICR） 中富集，我们再次观察到血液和靶组织之间 DMR 特征的复制。具体来说，我们在 Pb 暴露的雄性动物的血液和肝脏中观察到 Grb10 ICR 的高甲基化。结论 这些数据提供了初步证据，表明印记基因可能是寻找靶组织中毒物暴露的表观遗传生物标志物的可行候选者。需要对等位基因和发育阶段特异性效应，以及其他印记基因是否提供这种关系的更多例子进行进一步的研究。https://doi.org/10.1289/EHP14074。