A Prospective Exposome-Based Gene–Environment Interaction Study on the Effects of Prenatal Environmental Exposure on Fetal Growth in the Shanghai Birth Cohort

BACKGROUND: Both environmental exposure and type 2 diabetes (T2D) genetic susceptibility affect fetal growth. However, most previous studies used single exposure rather than an exposome strategy to explore the association between environmental factors and fetal growth, and the interactions of environmental exposures with maternal and fetal genes were often overlooked. OBJECTIVES: To explore the associations between a broad range of prenatal environmental factors and fetal growth and further evaluate the effect modification of maternal and fetal T2D genetic susceptibility on the identified exposures. METHODS: From 1,933 mother-neonate pairs from the Shanghai Birth Cohort, we estimated the associations between 70 prenatal exposure measures (including outdoor environment, residential environment, chemical exposures, lifestyle factors, and psychosocial status) and fetal growth, measured by birth-weight-for-gestational-age z-score (WAZ). Single-exposure analysis, elastic net regression, sparse partial least squares regression, extreme gradient boosting, and random forest were applied jointly to screen for WAZ-associated exposures. Multivariable linear regression models were used to assess the interactions of WAZ-associated exposures with maternal and fetal T2D polygenetic risk score (PRS). RESULTS: Sixteen prenatal exposures were associated with fetal growth, of which manganese, strontium, and residential greenspace showed a positive association while bisphenol A (BPA), 2,4-dihydroxy benzophenone (BP-1), ethyl 4-hydroxybenzoate (EtP), 4-hydroxybenzophenone (4-HBP), artificial light at night, noise, nitrogen dioxide, rubidium, thallium, silver, and humidity had a negative association. Temperature had an inverse U-shaped association with WAZ. The interactions of BPA and silver with maternal and fetal T2D PRS and rubidium with fetal T2D PRS were statistically significant, with more pronounced exposure effects in individuals with high T2D genetic risks. DISCUSSION: Our study identified several prenatal environmental exposures within the outdoor environment, phenols, and metal(loid)s that were associated with fetal growth. Mother-neonate pairs with high T2D genetic susceptibility were particularly vulnerable to the environmental insults. https://doi.org/10.1289/EHP15902.