Epigenetics in early life: placental promoter methylation in DNA repair genes and prenatal exposure to particulate air pollution

摘要

Background: Exposure to particulate air pollution has been linked to carcinogenic insult. DNA repair pathways are able to mend and maintain the correct DNA sequences. However, they have the potential to induce long-term effects when their functioning is compromised. In the context of the developmental origin of disease, we studied the placental mutation rate exemplified by mutations in the Alu gene in association with prenatal PM_2.5 exposure. Additionally, we investigated whether placental DNA methylation in the promoter region of key DNA repair genes and tumour suppressor genes was associated with PM_2.5 exposure. Methods: 463 newborn-mother pairs were selected at random from the ENVIRONAGE birth cohort. The placental mutation rate and methylation of key DNA methylation genes including APEX1, OGG1, PARP1, ERCC1, and ERCC4 was assessed We regressed DNA methylation profiles in association with the prenatal exposure over the entire pregnancy while adjusting for newborns' sex, ethnicity, maternal age, education, smoking habits, pre-pregnancy BMI, gestational age, date of delivery, and batch effect. Results: A higher relative placental DNA mutation rate of 2.97% in Alu (p = 0.029) was observed for an interquartile range (IQR) increase of 3.84 μg/m~3 in PM_2.5 level during the entire pregnancy. The relative promoter methylation of key DNA repair genes in the base excision repair pathway was 9.26% higher in APEX1 (p = 0.008) and 14.79% higher for OGG1 (p = 0.015) for an IQR increment in prenatal PM_2.5 exposure. However, no statistical significance was reached for PARP1. In the nucleotide excision repair pathway, a 14.88% increased promoter methylation was observed for ERCC4 (p = 0.005), whereas ERCC1 promoter methylation did not alter significantly with an IQR increment in prenatal PM_2.5 exposure. For the same exposure contrast we observed a relative increase of 10.72% (p = 0.001) in methylation for the promoter region of tumour suppressor gene p53, while promoter methylation of tumour suppressor candidate DAPK1 decreased by 13.65% (p = 0.011). Conclusions: In utero exposure to particulate matter is associated with a higher placental mutation rate in concert with newborn placental epigenetic alterations in key DNA repair and tumour suppressor genes. Future studies are essential to elucidate the persistence of these changes and their role in carcinogenic insults.