Incorporating maternal metabolome and genome to understand the effects of prenatal phenol exposure on the first 1000-day growth in an exposome-based study

Previous studies on prenatal environmental factors and early-life growth generally applied the single-exposure strategy, mostly relying on cross-sectional growth indicators. No attempt has been made to explore the environmental effects on longitudinal growth at the exposome level. Further, the underlying bio-mechanisms and gene-environment interactions are poorly understood. Within 1,944 mother-child pairs from the Shanghai Birth Cohort, neonatal sex-specific z-scores of weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) were used as the fetal growth outcomes. The growth trajectories of WAZ, LAZ, and WLZ before 2 years old were used as the child growth outcomes. We combined multiple exposome analysis strategies to screen for prenatal environmental factors that continuously affect the first 1000-day growth, based on which maternal metabolome and genome were incorporated to explore the underlying bio-mechanisms and effect modification by genetic predisposition. We found that phenols were the environmental factors that had a lasting growth impact, showing negative associations with neonatal WAZ, LAZ, and WLZ and positive associations with the risks of slow WAZ and LAZ growth trajectories and rapid WLZ growth trajectory in children. Metabolomic and gene-environment interaction analyses suggested the chemicals may exert such lasting effects by upregulating maternal glucose and lipid metabolism during pregnancy, and the effects were specifically more pronounced in mothers with high glucose and low lipid genetic predispositions. Our study suggests that prenatal exposure to phenols has lasting effects on offspring's first-1000-day growth by disturbing maternal glucose and lipid metabolism. The effects may be aggravated by maternal high glucose and low lipid genetic predispositions.