Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
PLoS One. 2022 May 2;17(5):e0267946. doi: 10.1371/journal.pone.0267946. eCollection 2022.
Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5-24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context of childhood obesity. These preliminary findings are consistent with Developmental Origins of Health and Disease paradigm, which posits that adverse prenatal exposures set developmental health trajectories.
母亲肥胖是儿童肥胖的一个重要危险因素，并影响后代代谢性疾病的患病率。由于儿童肥胖受产后因素影响，因此确定孕期肥胖女性所生的儿童在出生时是否存在可检测到的改变至关重要。表观遗传机制，如 DNA 甲基化修饰，被认为介导了产前编程。我们研究了来自母亲正常体重指数（BMI 18.5-24.9kg/m2）的男性和女性婴儿与肥胖母亲（BMI≥30kg/m2）的婴儿的 DNA 甲基化特征。BMI 在加拿大安大略省出生研究（OBS）中招募的女性在第一次产前就诊时进行测量，这些女性在多伦多西奈山医院分娩。从母亲正常 BMI 和肥胖的女性中采集新生儿足跟血样，这些女性在足月时进行了 24 小时的出生后足跟采血（总 n=40），并匹配了产次、年龄和新生儿性别。使用简化代表性双测序来识别与 CpG 密集区域中差异甲基化区域（DMR）相关的基因组位点，这些区域最有可能影响基因调控。DMR 主要定位于基因间区域和基因体，只有 9%的 DMR 定位于启动子区域。与 DMR 相关的基因与来自大型公开可用队列研究，即阿冯纵向研究父母和孩子（ALSPAC；总 n=859）的基因进行了比较。超几何检验显示，OBS 和 ALSPAC 队列中与 DMR 相关的基因存在显著重叠。PTPRN2，一个参与胰岛素分泌的基因，以及 MAD1L1，一个在细胞周期和肿瘤抑制中发挥作用的基因，在两个队列的男性和女性中都包含 DMR。在男性中，KEGG 途径分析显示，参与内吞作用和癌症途径的基因显著过表达，包括 IGF1R，先前的动物模型和儿童肥胖时的淋巴细胞研究表明，IGF1R 对饮食诱导的代谢应激有反应。这些初步发现与健康与疾病的发育起源范式一致，该范式假设不利的产前暴露会设定发育健康轨迹。
