Prepregnant Obesity of Mothers in a Multiethnic Cohort Is Associated with Cord Blood Metabolomic Changes in Offspring

Maternal obesity
has become a growing global health concern that
may predispose the offspring to medical conditions later in life.
However, the metabolic link between maternal prepregnant obesity and
healthy offspring has not yet been fully elucidated. In this study,
we conducted a case-control study using a coupled untargeted and targeted
metabolomic approach from the newborn cord blood metabolomes associated
with a matched maternal prepregnant obesity cohort of 28 cases and
29 controls. The subjects were recruited from multiethnic populations
in Hawaii, including rarely reported Native Hawaiian and other Pacific
Islanders (NHPI). We found that maternal obesity was the most important
factor contributing to differences in cord blood metabolomics. Using
an elastic net regularization-based logistic regression model, we
identified 29 metabolites as potential early-life biomarkers manifesting
intrauterine effect of maternal obesity, with accuracy as high as
0.947 after adjusting for clinical confounding (maternal and paternal
age, ethnicity, parity, and gravidity). We validated the model results
in a subsequent set of samples (N = 30) with an accuracy
of 0.822. Among the metabolites, six metabolites (galactonic acid,
butenylcarnitine, 2-hydroxy-3-methylbutyric acid, phosphatidylcholine
diacyl C40:3, 1,5-anhydrosorbitol, and phosphatidylcholine acyl-alkyl
40:3) were individually and significantly different between the maternal
obese and normal-weight groups. Interestingly, hydroxy-3-methylbutyric
acid showed significantly higher levels in cord blood from the NHPI
group compared to that from Asian and Caucasian groups. In summary,
significant associations were observed between maternal prepregnant
obesity and offspring metabolomic alternation at birth, revealing
the intergenerational impact of maternal obesity.

孕产妇肥胖已成为日益严峻的全球性公共卫生议题，可使子代在生命后期更易罹患各类疾病。然而，孕产妇孕前肥胖与子代健康之间的代谢关联尚未得到充分阐明。本研究采用非靶向与靶向联用的代谢组学分析策略，对28例孕前肥胖孕产妇（病例组）与29例体重正常孕产妇（对照组）匹配的新生儿脐带血代谢组开展病例-对照研究。研究对象招募自夏威夷的多种族人群，其中包括此前鲜有报道的夏威夷原住民及其他太平洋岛民（Native Hawaiian and other Pacific Islanders, NHPI）。研究发现，孕产妇肥胖是导致脐带血代谢组学特征产生差异的最关键因素。本研究基于弹性网络正则化逻辑回归模型，筛选出29种可作为孕产妇肥胖宫内效应潜在早期生物标志物的代谢物；在校正孕产妇年龄、父亲年龄、种族、产次及孕次等临床混杂因素后，模型预测准确率高达0.947。后续在30例独立样本中对该模型结果进行验证，验证准确率达0.822。在上述代谢物中，6种代谢物（半乳糖酸（galactonic acid）、烯基肉碱（butenylcarnitine）、2-羟基-3-甲基丁酸（2-hydroxy-3-methylbutyric acid）、二酰基磷脂酰胆碱C40:3（phosphatidylcholine diacyl C40:3）、1,5-脱水山梨醇（1,5-anhydrosorbitol）以及酰基烷基磷脂酰胆碱40:3（phosphatidylcholine acyl-alkyl 40:3））在肥胖孕产妇组与正常体重孕产妇组间均呈现显著的个体差异。值得注意的是，与亚裔及白人群体相比，NHPI组的脐带血中2-羟基-3-甲基丁酸（hydroxy-3-methylbutyric acid）水平显著更高。综上，本研究发现孕产妇孕前肥胖与新生儿出生时的子代代谢组学改变存在显著关联，揭示了孕产妇肥胖的代际影响。