TY - JOUR
T1 - Non-linear and non-additive associations between the pregnancy metabolome and birthweight
AU - Colicino, E.
AU - Ferrari, F.
AU - Cowell, W.
AU - Niedzwiecki, M. M.
AU - Foppa Pedretti, N.
AU - Joshi, A.
AU - Wright, R. O.
AU - Wright, R. J.
N1 - Funding Information:
This work was supported by the National Institutes of Health [grant numbers: R01 HL095606, R01 HL114396, and UG3 OD023337 supporting the cohort follow-up and data collection and statistical support through P30 ES023515 and UL1 TR001433. During the preparation of this manuscript, EC was supported by R01 ES032242, U2CES026555, U2CES026561, P30ES023515; FF was supported by R01 ES028804; and WC was supported by T32 HD049311 and K99ES032029].
Publisher Copyright:
© 2021
PY - 2021/11
Y1 - 2021/11
N2 - Background: Birthweight is an indicator of fetal growth and environmental-related alterations of birthweight have been linked with multiple disorders and conditions progressing into adulthood. Although a few studies have assessed the association between birthweight and the totality of exogenous exposures and their downstream molecular responses in maternal urine and cord blood; no prior research has considered a) the maternal serum prenatal metabolome, which is enriched for hormones, and b) non-linear and synergistic associations among exposures. Methods: We measured the maternal serum metabolome during pregnancy using an untargeted metabolomics approach and birthweight for gestational age (BWGA) z-score in 410 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. We leveraged a Bayesian factor analysis for interaction to select the most important metabolites associated with BWGA z-score and to evaluate their linear, non-linear and non-additive associations. We also assessed the primary biological functions of the identified proteins using the MetaboAnalyst, a centralized repository of curated functional information. We compared our findings with those of a traditional metabolite-wide association study (MWAS) in which metabolites are individually associated with BWGA z-score. Results: Among 1110 metabolites, 46 showed evidence of U-shape associations with BWGA z-score. Most of the identified metabolites (85%) were lipids primarily enriched for pathways central to energy production, immune function, and androgen and estrogen metabolism, which are essential for pregnancy and parturition processes. Metabolites within the same class, i.e. steroids and phospholipids, showed synergistic relationships with each other. Conclusions: Our results support that the aspects of the maternal metabolome during pregnancy contribute linearly, non-linearly and synergistically to variation in newborn birthweight.
AB - Background: Birthweight is an indicator of fetal growth and environmental-related alterations of birthweight have been linked with multiple disorders and conditions progressing into adulthood. Although a few studies have assessed the association between birthweight and the totality of exogenous exposures and their downstream molecular responses in maternal urine and cord blood; no prior research has considered a) the maternal serum prenatal metabolome, which is enriched for hormones, and b) non-linear and synergistic associations among exposures. Methods: We measured the maternal serum metabolome during pregnancy using an untargeted metabolomics approach and birthweight for gestational age (BWGA) z-score in 410 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. We leveraged a Bayesian factor analysis for interaction to select the most important metabolites associated with BWGA z-score and to evaluate their linear, non-linear and non-additive associations. We also assessed the primary biological functions of the identified proteins using the MetaboAnalyst, a centralized repository of curated functional information. We compared our findings with those of a traditional metabolite-wide association study (MWAS) in which metabolites are individually associated with BWGA z-score. Results: Among 1110 metabolites, 46 showed evidence of U-shape associations with BWGA z-score. Most of the identified metabolites (85%) were lipids primarily enriched for pathways central to energy production, immune function, and androgen and estrogen metabolism, which are essential for pregnancy and parturition processes. Metabolites within the same class, i.e. steroids and phospholipids, showed synergistic relationships with each other. Conclusions: Our results support that the aspects of the maternal metabolome during pregnancy contribute linearly, non-linearly and synergistically to variation in newborn birthweight.
KW - Birthweight
KW - Exposome
KW - Factor analysis for interaction
KW - Non-additive associations
KW - Nonlinear associations
KW - Prenatal metabolomics
UR - http://www.scopus.com/inward/record.url?scp=85109612333&partnerID=8YFLogxK
U2 - 10.1016/j.envint.2021.106750
DO - 10.1016/j.envint.2021.106750
M3 - Article
C2 - 34256302
AN - SCOPUS:85109612333
SN - 0160-4120
VL - 156
JO - Environment international
JF - Environment international
M1 - 106750
ER -