Associations between placental O6 -methylguanine DNA methyltransferase (MGMT) activity, air pollutants and birth outcomes

Introduction: Maternal exposure to air pollutants in the environment has been associated with poor birth outcomes. Nitrogen oxides (NOx) can generate toxic alkylating agents (AAs), that form O6-alkylguanine, a promutagenic and toxic DNA base modification. The DNA repair protein, O6- methylguanine-DNA methyltransferase (MGMT) transfers the alkyl group from the O6 position to the active site cysteine, and so provides protection against AA induced toxicity. Objectives: To determine the association between MGMT placental activity, air pollutant exposure and small for gestational age (SGA) births. Methods: 81 pregnant women residing in Greater Manchester for the duration of their pregnancy, opted for Elective Caesarean Section (ELCS) and consented for placenta sampling. MGMT activity was quantified in placental extracts using a radioisotopic [3H] methyl transfer assay that used calf thymus DNA methylated in vitro with N-nitroso-N- [3H]-methylurea, as the MGMT substrate. Participant’s postcodes and pollutant exposure for the duration of pregnancy was geocoded in ArcGIS. SGA was defined as <20 birthweight centile. Results: MGMT activity varied 6.8 fold (mean±SD 0.097 ± 0.03 fmole/mg protein). Mean exposure levels for participants during pregnancy were for NO2 32.1 ±7.8, NOx 55.2 ±14.5, PM2.5 17.4 ±0.7 and PM10 10.6 ±1.5 mg/m3, which were within Air Quality Standards Regulation. Associations were observed between SGA and NO2; 3 months prior to pregnancy OR 1.06 (95% CI 0.99e1.14), 1st trimester OR 1.05 (95% CI 0.99e1.11) and 2nd trimester OR 1.07 (95% CI 0.99e1.15). MGMT activity was not associated with SGA (p¼0.12) but was correlated with 2nd trimester PM10 (r2¼0.08, p¼0.01) and PM2.5 (r2¼0.09, p¼0.01) and inversely with 3rd trimester NOx (r2¼-0.08, p¼0.01). Conclusion: There is an association between NO2 and SGA, but this does not relate to placental DNA repair, measured by MGMT activity.