Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring

Abstract

Objectives:Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations.Methods:Between 2009–2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions.Results:After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (β-coefficient=−132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (β-coefficient=−135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight.Conclusion:We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.

Placental expression profile of imprinted genes impacts birth weight

“…The 9 imprinted genes we identified driving these phenotypes showed levels of expression that were, for the most part, positively associated with LGA status and include several genes previously implicated with birth weight. Genetic variants in H19, 13 methylation levels at differentially methylated regions (DMRs) of MEG3, 14 PLAGL1, [14][15][16] and IGF2/H19, 15,17 and protein levels of IGF2 18 have been observed to be relevant to birth weight, although the direction of the association with birth weight across these studies is not always consistent. For example, while paternally expressed IGF2 serum levels and mRNA expression levels have been positively associated with infant birth weight, 17,18 both positive and negative associations have been reported linking IGF2-DMR methylation with birth weight.…”

Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort

“…59 Our findings are consistent with those of previous studies in which FA intake before or/and during pregnancy or folate levels were associated with DNA methylation differences of a similar magnitude at this imprinted domain [46][47][48][49]60 and early childhood obesity. [61][62][63] Similar to the IGF2/H19 imprinted domain where IGF2 and H19 are reciprocally imprinted, the DLK1 and MEG3 genes, located on chromosome 14q32.2, are also reciprocally imprinted. 64 Methylation at the MEG3 DMR is established post-fertilization on the paternally derived allele, while methylation of the other DMRs is established in the gametes.…”

“…29 Differences in DNA methylation at the PLAGL1 DMR have been associated with chorioamnionitis and funisitis 68 as well as lower birth weight. 63 Aberrant epigenetic marks at this site are also associated with transient neonatal diabetes mellitus (TNDM), a disorder of growth restriction and hyperglycemia. 69,70 The PLAGL1 gene product is proposed to function as a major regulatory "hub" that coordinates the expression of a network of genes, including imprinted IGF2, H19, DLK1, MEG3 and MEST.…”

The effect of medical and operative birth interventions on child health outcomes in the first 28 days and up to 5 years of age: A linked data population‐based cohort study

“…The Extended Hygiene Hypothesis (EHH) hypothesizes that infants born by cesarean delivery have different colonization of the gut flora compared with infants born by vaginal birth. This may potentially affect the neonatal immune response 8, 9. The EPIgenetic Impact of Childbirth (EPIIC) hypothesis raises concern over the effects of stress (too high and too low) caused by medical and operative birth interventions to the epigenetic regulation of gene expression in the immune system 10, 11…”