Unknown,Transcriptomics,Genomics,Proteomics

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Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren

ABSTRACT: We report that the DNA methylation profile of a child’s neonatal whole blood can be significantly influenced by his or her mother’s neonatal blood lead levels (BLL). We recruited 35 mother-infant pairs in Detroit and measured the whole blood lead (Pb) levels and DNA methylation levels at over 450,000 loci from current blood and neonatal blood from both the mother and the child. We found that mothers with high neonatal BLL correlate with altered DNA methylation at 564 loci in their children’s neonatal blood. Our results suggest that Pb exposure during pregnancy affects the DNA methylation status of the fetal germ cells, which leads to altered DNA methylation in grandchildren’s neonatal dried blood spots. This is the first demonstration that an environmental exposure in pregnant mothers can have an epigenetic effect on the DNA methylation pattern in the grandchildren. For the study, we selected 35 dried blood spots (DBS) collected from mother-infant pairs from Health Fairs ran in three Detroit communities, because they have a high prevalence (8-11%) of high BLL in children. The sample set consisted of 25 male children and 18 female children. We also collected the neonatal DBS and mother neonatal DBS for these mother-infant pairs from the Michigan Neonatal Biobank. Then we measured a blood lead levels in dried blood spots using using atomic absorbtion spectrophotometry. Finally we measured the DNA methylation levels using human methylation 450K array from Illumina. Then we normalized the data for technical biases and tried to infer the the locus specific DNA methylation changes due to Pb exposure which was carried over from the grandmothers to the grandchildren by the Pb –exposed fetal germ cells of the mother using statistical model proposed by Sofer et al, 2012.

ORGANISM(S): Homo sapiens

SUBMITTER: Douglas Ruden

PROVIDER: E-GEOD-67444 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Prenatal exposure to neurotoxicants such as lead (Pb) may cause stable changes in the DNA methylation (5mC) profile of the fetal genome. However few studies have examined its effect on the DNA de-methylation pathway, specifically the dynamic changes of the 5-hydroxymethylcytosine (5hmC) profile. Therefore, in this study, we investigate the relationship between Pb exposure and 5mC and 5hmC modifications during early development. To study the changes in the 5hmC profile, we use a novel modification of the Infinium™ Human methylation 450K assay (Illumina, Inc.), which we named HMeDIP-450K assay, in an in vitro human embryonic stem cell model of Pb-exposure. We model Pb-exposure associated 5hmC changes as clusters of correlated, adjacent CpG sites, which are co-responding to Pb. We further extend our study to look at Pb-dependent changes in high density 5hmC regions in umbilical cord blood DNA from 48 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. For our study, we randomly selected UCB from 24 male and 24 female children from the 1st and 4th quartiles of Pb levels. Our data show that Pb-associated changes in the 5hmC and 5mC profiles can be divided into sex-dependent and sex-independent categories. Interestingly, differential 5mC sites are better markers of Pb-associated sex-dependent changes compared to differential 5hmC sites. In this study we identified several 5hmC and 5mC genomic loci, which we believe might have some potential as early biomarkers of prenatal Pb-exposure. Human Methylation 450K array coupled with 5-hydroxymethylcytosine (5hmC) IP or HMeDIP-450K array, was used to determine the high density 5hmC profile of 46 Umbilical cord blood samples from the ELLEMENT cohort. HM450K array, without IP was used to determine the 5-methylcytosine(5mC) plus 5hmC profile. The 5hmC region detected from the HMeDIP-450K array was subtracted from the HM450K(without IP) to get putative high density 5mC regions.

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Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren

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