Prenatal metabolomic profiles mediate the effect of maternal obesity on early childhood growth trajectories and obesity risk: the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study

Abstract

Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms. The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity. We included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study (CANDLE) pregnancy cohort. Liquid chromatography-mass spectrometry was used to conduct metabolomic profiling on the maternal plasma samples of the second trimester. The childhood growth outcomes of interest included body mass index (BMI) trajectories from birth to age 4 (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian Randomization (MR) method. Among 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4, respectively, and five of those mediated both outcomes. The MR analysis suggested six of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2, N2-dimethylguanosine). Our study provided further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways including identified metabolite mediators might provide novel intervention targets for preventing the intrauterine development of obesity in offspring of mothers with obesity.