Air pollution, placental DNA damage and repair and pilot study of effects on pregnancy outcomes

Abstract

The adverse effects of air pollution on pregnancy outcomes have become established over the past decade, but their mechanistic basis remains to be determined. Air pollution may increase exposure to toxic alkylating agents (AAs) either directly through the reaction of NOx with amines or indirectly through PM2.5 induced nitrosative stress. AAs induce the formation of the toxic, pro-mutagenic and pro-carcinogenic DNA adduct, O6-alkylguanine. This adduct is repaired by the DNA repair, O6-methylguanine-DNA methyltransferase (MGMT), which then provides protection against AAs induced toxicity. The role, if any, of AAs in the aetiology of adverse pregnancy outcomes is unknown. The aim of this study was to explore the associations between placental DNA damage, MGMT repair and exposure to air pollutants and pregnancy outcomes. Placental tissues were collected at St. Mary’s Hospital, Manchester from women who opted for Elective Caesarean Section delivery between 4th June 2015 and 13th May 2016. Pregnancy outcome data were obtained from routinely collected records. Air pollutant data, from stationary monitoring stations, was used to estimate exposure levels at the participants’s home address using a spatio-temporal model. Placental MGMT activity was quantified by a standard O6-alkylguanine-DNA alkyltransferase assay. The placental metabolome was analysed by High Performance Liquid Chromatography-High Resolution Mass Spectrometry (HPLC-HRMS) and Nuclear Magnetic Resonance (1H NMR) and placental DNA adduct by HPLC-HRMS and HPLC Tandem Quadrupole Mass Spectrometry (MS/MS). In this pilot study, we found air pollutant levels were associated with placental MGMT activity and DNA adduct levels in a trimester dependent fashion. NOx levels in the third trimester were negatively associated with MGMT activity and positively associated with DNA adducts in the first trimester. PM2.5 levels in the first and third trimester were positively associated with certain DNA adducts but not placental MGMT activity. The metabolic profiling showed a significant difference in metabolite features between exposure groups but no metabolite was identified. These associations, however, may not be biologically significant due to a lack of consistency and may simply be chance findings given the relatively small numbers of samples analysed. Nevertheless, this study provides preliminary knowledge/platform for placental DNA damage and repair research in relation to air pollutant and pregnancy outcomes. Future work would require the collection of larger numbers of placental samples and with a more diverse range of air pollutant levels to provide results with a biological meaning.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Povey (Supervisor) & Edward Johnstone (Supervisor)