Division of Epidemiology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC 27710, USA.
Int J Obes (Lond). 2013 Jul;37(7):907-13. doi: 10.1038/ijo.2013.47. Epub 2013 Mar 28.
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.
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.
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.
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.
低出生体重（LBW）与常见的成人发病慢性疾病有关，包括肥胖、心血管疾病、II 型糖尿病和某些癌症。LBW 的病因是多因素的。然而，最近的证据表明，暴露于抗生素也可能增加 LBW 的风险。这种关联的机制尚不清楚，尽管假设了表观遗传机制。在这项研究中，我们评估了母亲使用抗生素与 LBW 之间的关联，并研究了控制生长调节印迹基因的 DNA 甲基化改变在这些关联中的潜在作用。
在 2009-2011 年间，招募了 397 名孕妇并随访至分娩。通过母亲自我报告确定产前抗生素使用情况。使用亚硫酸氢盐焦磷酸测序在差异甲基化区域（DMRs）测量印迹基因的甲基化水平。使用广义线性模型检验抗生素使用、出生体重和 DMR 甲基化分数之间的关联。
在调整了婴儿性别、种族/民族、母体体重指数、分娩方式、妊娠期体重增加、分娩时的孕龄、叶酸摄入、体力活动、母亲吸烟和产次后，与非抗生素使用相比，怀孕期间使用抗生素与出生体重低 138 克相关（β系数=-132.99，s.e.=50.70，P=0.008）。在报告使用抗生素而不是青霉素的女性的新生儿中，这些关联最强（β系数=-135.57，s.e.=57.38，P=0.02）。五个 DMR 的甲基化，IGF2（P=0.05）、H19（P=0.15）、PLAGL1（P=0.01）、MEG3（P=0.006）和 PEG3（P=0.08），与母亲使用抗生素有关；其中，只有 PLAGL1 DMR 的甲基化也与出生体重有关。
我们报告了宫内暴露于抗生素与婴儿出生体重较低之间的负相关，并提供了支持这些关联中印迹基因可塑性的首个经验证据。
