Epigenetic mechanisms are thought to underlie the fetal programming of disease. A number of prenatal risk factors have been implicated in childhood asthma, and the possibility that prenatal epigenetic effects might be important in asthma has been mooted before(1). However, whilst there are indirect clues in support of this hypothesis, such as evidence for maternal line inheritance of asthma suggestive of imprinting, and data indicating transgenerational effects of grand-maternal smoking in pregnancy on asthma risk(2), direct evidence is currently lacking. We have found a positive association between prenatal paracetamol exposure and risk of asthma in ALSPAC and proposed that the underlying mechanism involves glutathione (GSH) depletion(3). This effect has become stronger for asthma at 91 months (odds ratio per category increase in paracetamol exposure 1.33 (95% CI: 1.15 to 1.54), P=0.000092), and the effect was modified by glutathione S-transferase (GST) M1 genotype in the mother and child (odds ratio 3.63 (1.48 to 8.92), P=0.005 if mother homozygous wild (HW) for GSTM1; OR 5.01 (2.13 to 11.74), P=0.00021 if child HW). Given that GSH depletion is thought to impair DNA methylation(4), and epigenetic mechanisms are thought to underlie fetal programming, we speculate that DNA hypomethylation may underlie the effect of prenatal paracetamol on asthma risk observed in ALSPAC.

Hypotheses

1) Prenatal paracetamol exposure leads to DNA hypo-methylation

2) Children with asthma have less DNA methylation than those without asthma