Upregulation of placental genes in the Aryl Hydrocarbon Receptor Pathway with Prenatal Tobacco Smoke Exposure

Abstract

Background: Smoking during pregnancy increases the risk for growth restriction and children’s health outcomes. Epigenomic studies have identified multiple genes within the aryl hydrocarbon receptor (Ahr) pathway as being differentially methylated in response to prenatal tobacco exposure, but it is unclear whether this exposure affects the functional activity of the Ahr pathway. This pathway has also been associated with multiple health outcomes, making it a strong candidate pathway for targeted studies of prenatal tobacco smoke exposure. We aimed to study whether placental expression of genes in the Ahr pathway are responsive to maternal cigarette use during pregnancy and whether this response correlates with dose.Methods: This study included 68 mothers (34 that smoked throughout pregnancy), from which placental gene expression was quantified via RNA-seq. Of the 46 genes that comprise the Ahr Pathway, 34 were detectable and passed QC metrics. We regressed normalized gene-expression on smoking status while adjusting for covariates and surrogate variables. We performed secondary analyses to test whether expression was associated with total cigarettes throughout pregnancy and cotinine concentrations.Results: Four genes within the Ahr pathway, TGFB1, CYP1A1, CYP1A2, and CYP1B1, exhibited increased expression in association with smoking during pregnancy (FDR < 0.05). Among smokers, cumulative dose of cigarettes throughout pregnancy, and average cotinine across three timepoints, was associated with increased expression, particularly for TGFB1 and CYP1A2 (p-value < 0.05).Conclusions: Placental Ahr-pathway genes, particularly TGFB1 and CYP1A1, are up-regulated in response to maternal smoking during pregnancy. TGFB1 is a multifunctional cytokine with critical roles in developmental processes, while CYP1A1 is the primary xenobiotic metabolizing enzyme in the placenta, and others have shown that elevated placental CYP1A1 is associated with adverse pregnancy outcomes. These may represent some of the functional responses of the placenta to prenatal tobacco exposure and potential intermediates on the path to pregnancy outcomes.