Prenatal Substance Exposure Is Associated with Increased Placental DRD1 Dopamine Receptor Gene Expression and Striatal Gray Matter Volume in Children

Background/Objectives: Prenatal substance exposure (PSE) to alcohol, cannabis, and other psychoactive drugs affects over 500,000 pregnancies annually in the US and is consistently associated with adverse birth and childhood outcomes, but the underlying biological mechanisms are not well-understood. Given the dopaminergic system’s role in substance use and child development, this study aimed to examine and connect the effects of PSE on dopaminergic placental gene expression at birth and on striatal brain volumes in middle childhood. We hypothesized that PSE would lead to reduced dopamine receptor D1 (DRD1) gene expression and smaller striatal gray-matter volumes (GMVs) and that placental DRD1 gene expression would be positively associated with striatal GMV. Methods: PSE, placental gene expression, and T1-weighted MRI data were drawn from a pilot study (n = 34) within the longitudinal cohort Stress in Pregnancy study. PSE was defined by any amount of alcohol, tobacco, or cannabis use during pregnancy. Results: Unexpectedly, children with PSE had a trend toward increased placental DRD1 gene expression (β = 0.497, p = 0.056) and significantly larger GMV in the right putamen (β = 0.374, p = 0.018) and nucleus accumbens (NAc) (β = 0.389, p = 0.029) than unexposed children. Independent of PSE, higher placental DRD1 gene expression at birth was also associated with larger right NAc GMV (β = 0.617, p = 0.015) in middle childhood. Conclusions: These findings contrast prior cross-sectional work linking high-dosage PSE to smaller striatal volumes and inconsistent patterns of dopaminergic gene expression, suggesting potential compensatory placental mechanisms reflected in biological outcomes across child development.