Parental Smoking and Risk of Childhood Brain Tumors by Functional Polymorphisms in Polycyclic Aromatic Hydrocarbon Metabolism Genes

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>We found positive interaction odds ratios (ORs) for both maternal and paternal smoking during pregnancy, <i>EPHX1</i> H139R, and childhood brain tumors (<i>P</i>_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 <i>EPHX1</i> H139R high-risk genotype only (OR_{no exposure} = 1.0; OR_≤3_hours/day = 1.32, 95% CI: 0.52–3.34; OR_>3hours/day = 3.18, 95% CI: 0.92–11.0; <i>P</i>_trend = 0.07).</p><p>Conclusion</p><p>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.</p></div

Risk of Childhood Brain Tumors by <i>EPHX1</i> H139R Genotype and Exposure to Parental Smoking (Maternal/Paternal), West Coast Childhood Brain Tumor Study, Born 1978–1990.

<p>Risk of Childhood Brain Tumors by <i>EPHX1</i> H139R Genotype and Exposure to Parental Smoking (Maternal/Paternal), West Coast Childhood Brain Tumor Study, Born 1978–1990.</p

Risk of Childhood Brain Tumors in Relation to Paternal Smoking during pregnancy by PAH Metabolism Genotype, West Coast Childhood Brain Tumor Study, Born 1978–1990.

a<p>Interaction between genotype and smoking, using dichotomous genotype and exposure levels never and ever.</p>b<p>Adjusted for race, sex, age at diagnosis, mother’s education, birth year and center.</p>c<p>Additionally adjusted for maternal smoking.</p>d<p>Microsomal epoxide hydrolase (mEH) activity: low–0,1 or 2 stable alleles (HH/HH, HH/HR, HY/HH, HH/RR, HY/HR, YY/HH); high–3 or 4 stable alleles (HY/RR, YY/HR, YY/RR).</p>e<p>Missing gene information for 1 control.</p>f<p>Missing gene information for 1 case.</p

Risk of Childhood Brain Tumors in Relation to Exposure to Parental Smoking during pregnancy, West Coast Childhood Brain Tumor Study, Born 1978–1990.

a<p>Odds ratio and 95% CI, adjusted for race, sex, age at diagnosis/reference, mother’s education, birth year and center.</p>b<p>Excludes children exposed to only paternal or other passive smoking.</p>c<p>Other passive is exposure to tobacco smoke from a household resident other than the father, or at the workplace.</p>d<p>Excludes children exposed to only maternal or other passive smoking.</p>e<p>Hours per day of exposure from the father only, or from the father and another source.</p

Risk of Childhood Brain Tumors in Relation to Paternal Smoking Level during pregnancy by Polymorphisms in Selected Genes, West Coast Childhood Brain Tumor Study, Born 1978–1990.

a<p>Hours of exposure per day.</p>b<p>Adjusted for race, sex, age at diagnosis/reference, mother’s education, birth year and center.</p>c<p>Additionally adjusted for maternal smoking.</p>d<p>Interaction between genotype and smoking, using hours of exposure per day (interaction for trend).</p>e<p>Microsomal epoxide hydrolase (mEH) activity: low–0,1 or 2 stable alleles (HH/HH, HH/HR, HY/HH, HH/RR, HY/HR, YY/HH); high–3 or 4 stable alleles (HY/RR, YY/HR, YY/RR).</p

Demographic Characteristics of Children With and Without Brain Tumors, West Coast Childhood Brain Tumor Study, Born 1978–1990.

a<p>Reference age for controls.</p>b<p>c</p><p>Primitive neuroectodermal tumor.</p

Characteristics of Candidate Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism Genes.

<p>Characteristics of Candidate Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism Genes.</p

Examples of most differentially regulated single genes.

<p>Examples of most differentially regulated single genes.</p

Histopathology of the fetal lungs are shown on the left for a saline control with lung score of 0 (A, C, E, G) and on the right for a GBS animal with severe fetal lung injury and lung score of 4 (B, D, F, H).

<p>Panels show hematoxylin and eosin staining (A, B), Leder staining for neutrophils (C, D), CD68 staining for macrophages (E, F), and Masson’s Trichrome staining for collagen (G, H).</p

IPA diagrams were generated for A) neutrophil chemotaxis Gene Ontology gene set and B) NF-κB, a transcription factor predicted to be activated by IPA.

<p>Genes shown were filtered for interactions reported in humans only and presented by cellular localization. Direct and indirect interactions are shown by solid lines and dashed lines respectively. Green indicates gene downregulation and red depicts upregulation. White symbols indicate functionally associated neighboring genes that were not differentially expressed in the data. Color intensity represents the average of log2 fold change with brighter colors representing a more significant difference between GBS and controls. Symbols for each molecule are presented according to molecular functions and type of interactions.</p