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 exposure with
maternal and fetal genes were often overlooked. OBJECTIVES: We explore the associations between a broad range of prenatal environmental
factors and fetal growth and further evaluate the effect of 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-dihydroxybenzophenone (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 a high T2D genetic susceptibility were particularly vulnerable
to environmental insults.