BACKGROUND: A recent meta-analysis suggested an association between exposure to 
paternal smoking during pregnancy and childhood brain tumor risk, but no studies 
have evaluated whether this association differs by polymorphisms in genes that 
metabolize tobacco-smoke chemicals.
METHODS: We assessed 9 functional polymorphisms in 6 genes that affect the 
metabolism of polycyclic aromatic hydrocarbons (PAH) to evaluate potential 
interactions with parental smoking during pregnancy in a population-based 
case-control study of childhood brain tumors. Cases (N = 202) were ≤10 years 
old, diagnosed from 1984-1991 and identified in three Surveillance, 
Epidemiology, and End Results (SEER) registries in the western U.S. Controls in 
the same regions (N = 286) were frequency matched by age, sex, and study center. 
DNA for genotyping was obtained from archived newborn dried blood spots.
RESULTS: We found positive interaction odds ratios (ORs) for both maternal and 
paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors 
(P(interaction) = 0.02; 0.10), such that children with the high-risk (greater 
PAH activation) genotype were at a higher risk of brain tumors relative to 
children with the low-risk genotype when exposed to tobacco smoke during 
pregnancy. A dose-response pattern for paternal smoking was observed among 
children with the EPHX1 H139R high-risk genotype only (OR(no exposure) = 1.0; 
OR(≤3 hours/day) = 1.32, 95% CI: 0.52-3.34; OR(>3 hours/day )= 3.18, 95% CI: 
0.92-11.0; P(trend )= 0.07).
CONCLUSION: Parental smoking during pregnancy may be a risk factor for childhood 
brain tumors among genetically susceptible children who more rapidly activate 
PAH in tobacco smoke.