Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study

Abstract

Pre-pregnancy obesity is an established risk factor for adverse sex-specific cardiometabolic health in offspring. Epigenetic alterations, such as in DNA methylation (DNAm), are a hypothesized link; however, sex-specific epigenomic targets remain unclear. Leveraging data from the Newborn Epigenetics Study (NEST) cohort, linear regression models were used to identify CpG sites in cord blood leukocytes associated with pre-pregnancy obesity in 187 mother-female and 173 mothermale offsprings. DNAm in cord blood was measured using the Illumina HumanMethylation450k BeadChip. Replication analysis was conducted among the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Associations between pre-pregnancy obesity-associated CpG sites and offspring BMI z-score (BMIz) and blood pressure (BP) percentiles at 4-5-years of age were also examined. Maternal pre-pregnacy obesity was associated with 876 CpGs in female and 293 CpGs in male offspring (false discovery rate <5%). Among female offspring, 57 CpG sites, including the top 18, mapped to the TAPBP gene (range of effect estimates: −0.83% decrease to 4.02% increase in methylation). CpG methylation differences in the TAPBP gene were also observed among males (range of effect estimates: −0.30% decrease to 2.59% increase in methylation). While technically validated, none of the TAPBP CpG sites were replicated in ALSPAC. In NEST, methylation differences at CpG sites of the TAPBP gene were associated with BMI z-score (cg23922433 and cg17621507) and systolic BP percentile (cg06230948) in female and systolic (cg06230948) and diastolic (cg03780271) BP percentile in male offspring. Together, these findings suggest sexspecific effects, which, if causal, may explain observed sex-specific effects of maternal obesity. ARTICLE HISTORY

Prenatal oxidative balance and risk of asthma and allergic disease in adolescence

“…Mechanisms for oxidative stress resulting from increased maternal BMI are also well known 35 and are driven by production of proinflammatory chemokines, adipokines (ie, leptin), and innate inflammatory cytokines (ie, TNF-a and IL-6) from adipose tissue. Prenatal exposures to maternal smoking, 36 acetaminophen intake, 37 and greater BMI 38 have all been linked to altered DNA methylation profiles, suggesting that the influence of these pro-oxidant fetal exposures on disease outcomes might be mediated by alterations in the epigenome.…”

Maternal Obesity Programs Offspring Development and Resveratrol Potentially Reprograms the Effects of Maternal Obesity

“…In mammals, early embryogenesis is a critical period for the establishment of the epigenome [14]. Maternal obesity may influence the placenta and offspring epigenetic landscape [15,16]. Ge et al found that DNA methylation in differential methylation regions of Peg3 is altered in spermatozoa of offspring from obese mothers, but is not affected in spermatozoa of offspring from diabetic mothers [17].…”

Sex differences in the association between prenatal exposure to maternal obesity and hippocampal volume in children

“…First, estrogen has been shown to have anti‐inflammatory properties and may reduce cytokine exposure as well as protect against fat accumulation in the brain of female fetuses specifically (Argente‐Arizón et al, ; Kim, Young, Grattan, & Jasoni, ; Tiwari‐Woodruff & Voskuhl, ; Zhu et al, ). Second, because an adverse in utero environment may result in altered epigenetic modifications to the X‐chromosome and could specifically impact X‐linked genes important for brain development, females may be more protected by having two X‐chromosomes (Cox et al, ; Glendining & Jasoni, ; Martin et al, ; Schellong et al, ).…”