Neighborhood and Family Environment of Expectant Mothers May Influence Prenatal Programming of Adult Cancer Risk: Discussion and an Illustrative DNA Methylation Example

Abstract

Childhood stressors including physical abuse predict adult cancer risk. Prior research portrays this finding as an indirect mechanism that operates through coping behaviors, including adult smoking, or through increased toxic exposures during childhood. Little is known about potential direct causal mechanisms between early-life stressors and adult cancer. Because prenatal conditions can affect gene expression by altering DNA methylation, with implications for adult health, we hypothesize that maternal stress may program methylation of cancer-linked genes during gametogenesis. To illustrate this hypothesis, we related maternal social resources to methylation at the imprinted MEG3 differentially methylated regulatory region, which has been linked to multiple cancer types. Mothers (n = 489) from a diverse birth cohort (Durham, North Carolina) provided newborns’ cord blood and completed a questionnaire. Newborns of currently married mothers showed lower (−0.321 SD, p < .05) methylation compared to newborns of never-married mothers, who did not differ from newborns whose mothers were cohabiting and others (adjusted for demographics). MEG3 DNA methylation levels were also lower when maternal grandmothers co-resided before pregnancy (−0.314 SD, p < .05). A 1-SD increase in prenatal neighborhood disadvantage also predicted higher methylation (−0.137 SD, p < .05). In conclusion, we found that maternal social resources may result in differential methylation of MEG3, which demonstrates a potential partial mechanism priming socially disadvantaged newborns for later risk of some cancers.

Notes

¹ As a check to explore if household composition is confounded by unobserved factors, in supplementary analyses (Supplementary Table 2) using two-stage least squares regression, we verified that selection into household composition by sociodemographics can explain the household composition results (i.e., we are not suggesting single motherhood causes cancer in offspring). Maternal relationship status per se is likely not causally related to DNA methylation, but rather mothers and romantic partners likely tend to offer social support to the mother. To assess the potential for causality, a supplementary two-stage least squares model with an overlapping set of covariates was used to predict aspects of household composition, and residuals from these models were used to replace household composition in the analytic model. Results from that model show no remaining associations between MEG3 DMR methylation and household composition and thus do not support a causal interpretation.

Additional information

Funding

This work was based on the Newborn Epigenetic STudy supported by National Institute of Environmental Health Sciences of the National Institutes of Health under award number R01ES016772 (PI: Hoyo). This work was supported in part by an appointment (King) to the Research Participation Program for the U.S. Environmental Protection Agency, Office of Research and Development, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the EPA, and in part by a fellowship from the National Cancer Institute under award number R25CA126938 (Scarbrough). This work also received support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K99 HD075860, PI: Kane), the National Institute of Environmental Health Sciences (P01ES022831, PI/PD Murphy), and the USEPA (RD-83543701, PI/PD Murphy), and general support from the Population Research Infrastructure Program (R24 HD050924), awarded to the Carolina Population Center at the University of North Carolina at Chapel Hill. This work does not represent the official views of the Environmental Protection Agency.