Susan Searles Nielsen

Risk of brain tumors in children and susceptibility to organophosphorus insecticides: the potential role of paraoxonase (PON1).

Prior research suggests that childhood brain tumors (CBTs) may be associated with exposure to pesticides. Organophosphorus insecticides (OPs) target the developing nervous system, and until recently, the most common residential insecticides were chlorpyrifos and diazinon, two OPs metabolized in the body through the cytochrome P450/paraoxonase 1 (PON1) pathway. To investigate whether two common PON1 polymorphisms, C-108T and Q192R, are associated with CBT occurrence, we conducted a population-based study of 66 cases and 236 controls using DNA from neonatal screening archive specimens in Washington State, linked to interview data. The risk of CBT was nonsignificantly increased in relation to the inefficient PON1 promoter allele [per PON1-108T allele, relative to PON1-108CC: odds ratio (OR) = 1.4; 95% confidence interval (CI), 1.0–2.2; p-value for trend = 0.07]. Notably, this association was strongest and statistically significant among children whose mothers reported chemical treatment of the home for pests during pregnancy or childhood (per PON1-108T allele: among exposed, OR = 2.6; 95% CI, 1.2–5.5; among unexposed, OR = 0.9; 95% CI, 0.5–1.6) and for primitive neuroectodermal tumors (per PON1-108T allele: OR = 2.4; 95% CI, 1.1–5.4). The Q192R polymorphism, which alters the structure of PON1 and influences enzyme activity in a substrate-dependent manner, was not associated with CBT risk, nor was the PON1C-108T/Q192R haplotype. These results are consistent with an inverse association between PON1 levels and CBT occurrence, perhaps because of PON1’s ability to detoxify OPs common in children’s environments. Larger studies that measure plasma PON1 levels and incorporate more accurate estimates of pesticide exposure will be required to confirm these observations.

Childhood brain tumors, residential insecticide exposure, and pesticide metabolism genes.

Background Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals. Methods We analyzed population-based case–control data to examine whether CBT is associated with the functional genetic polymorphisms PON1C–108T, PON1Q192R, PON1L55M, BCHEA539T, FMO1C–9536A, FMO3E158K, ALDH3A1S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, ≤ 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview. Results We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1–108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1–3.0] and FMO1–9536A (*6) allele (OR = 2.7; 95% CI, 1.2–5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5–1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6–1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHEA539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children. Conclusion Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.

Environmental tobacco smoke and Parkinson's disease

Parkinsons disease is inversely associated with cigarette smoking, but its relation with passive smoking or environmental tobacco smoke exposure is rarely examined.

Nicotine from edible Solanaceae and risk of Parkinson disease

To test whether risk of Parkinson disease (PD) is associated with consumption of nicotine‐containing edibles from the same botanical family as tobacco, Solanaceae, including peppers, tomatoes, and potatoes.

Is ethnicity associated with morphine's side effects in children? morphine pharmacokinetics, analgesic response and side effects in children having tonsillectomy

Objectives/Aims:  To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid‐related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non‐Latino Caucasian (NL) children.

Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease

Overview The etiology of Parkinson disease (PD) involves both genetic susceptibility and environmental exposures. In particular, coffee consumption is inversely associated with PD but the mechanisms underlying this intriguing association are unknown. According to a recent genome-wide gene–environment interaction study, the inverse coffee–PD association was two times stronger among carriers of the T allele of SNP rs4998386 in gene GRIN2A than in homozygotes for the C allele. We attempted to replicate this result in a similarly sized pooled analysis of 2,289 cases and 2,809 controls from four independent studies (Denmark, France, Seattle-United States (US), and Rochester-US) with detailed caffeinated coffee consumption data and rs4998386 genotypes. Using a variety of definitions of coffee drinking and statistical modeling techniques , we failed to replicate this interaction. Notably, whereas in the original study there was an association between rs4998386 and coffee consumption among controls, but not among cases, none of the datasets analyzed here indicated an association between rs4998386 and coffee consumption among controls. Based on large, well-characterized datasets independent from the original study, our results are not in favor of an interaction between caffeinated coffee consumption and rs4998386 for PD risk and suggest that the original finding may have been driven by an association of coffee consumption with rs4998386 in controls. The next years will likely see an increasing number of papers examining gene–environment interactions at the genome-wide level, which poses important methodological challenges. Our findings underline the need for a careful assessment of the findings of such studies.

Family cancer history and risk of brain tumors in children: results of the SEARCH international brain tumor study

ObjectiveTo examine whether childhood brain tumors (CBTs) are associated with a family history of brain tumors or other cancers in an international case–control study.MethodsCancers in children’s first- and second-degree relatives were ascertained by interview with parents of 620 children with astroglial tumors, 255 with primitive neuroectodermal tumors, 324 with other CBTs, and 2,218 controls from Australia, Canada, France, Israel, Italy, Spain, and the US. These were used with histories of neurofibromatosis or tuberous sclerosis to exclude in subanalyses children with Li-Fraumeni or other hereditary syndromes predisposing to brain tumors.ResultsA first- or second-degree relative of 4% of children with astroglial tumors, 6% with PNET, 5% with other CBTs, and 5% of controls had had a brain tumor. Any potential differences were statistically non-significant, including when focusing on relatives diagnosed in childhood. In the US, where anatomical sites of relatives’ other cancers were known, CBT occurrence was not associated with any other specific site. Results were not markedly altered by exclusion of children with hereditary syndromes.ConclusionConsistent with most prior studies using these methods, we observed no strong relationship between CBT occurrence and cancers in family members.

Childhood Brain Tumors and Maternal Cured Meat Consumption in Pregnancy: Differential Effect by Glutathione S-Transferases

Background: Some epidemiologic studies suggest that maternal consumption of cured meat during pregnancy may increase risk of brain tumors in offspring. We explored whether this possible association was modified by fetal genetic polymorphisms in genes coding for glutathione S-transferases (GSTs) that may inactivate nitroso compounds. Methods: We assessed six GST variants: GSTM1 null, GSTT1 null, GSTP1I105V (rs1695), GSTP1A114V (rs1138272), GSTM3*B (3-bp deletion), and GSTM3A-63C (rs1332018) within a population-based case-control study with data on maternal prenatal cured meat consumption (202 cases and 286 controls born in California or Washington, 1978–1990). Results: Risk of childhood brain tumor increased with increasing cured meat intake by the mother during pregnancy among children without GSTT1 [OR = 1.29; 95% confidence interval (95% CI), 1.07–1.57 for each increase in the frequency of consumption per week] or with potentially reduced GSTM3 (any −63C allele; OR = 1.14; 95% CI, 1.03–1.26), whereas no increased risk was observed among those with GSTT1 or presumably normal GSTM3 levels (interaction P = 0.01 for each). Conclusions: Fetal ability to deactivate nitrosoureas may modify the association between childhood brain tumors and maternal prenatal consumption of cured meats. Impact: These results support the hypothesis that maternal avoidance during pregnancy of sources of some nitroso compounds or their precursors may reduce risk of brain tumors in some children. Cancer Epidemiol Biomarkers Prev; 20(11); 2413–9. ©2011 AACR.

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

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 (ORno 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; 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.

Blood α-synuclein in agricultural pesticide handlers in central Washington State

Epidemiologic studies suggest that occupational exposure to pesticides might increase Parkinson disease risk. Some pesticides, such as the organophosphorus insecticide chlorpyrifos, appear to increase the expression of α-synuclein, a protein critically involved in Parkinson disease. Therefore, we assessed total blood cell α-synuclein in 90 specimens from 63 agricultural pesticide handlers, mainly Hispanic men from central Washington State, who participated in the states cholinesterase monitoring program in 2007-2010. Additionally, in age-adjusted linear regression models for repeated measures, we assessed whether α-synuclein levels were associated with butyrylcholinesterase-chlorpyrifos adducts or cholinesterase inhibition measured in peripheral blood, or with self-reported pesticide exposure or paraoxonase (PON1) genotype. There was no evidence by any of those indicators that exposure to chlorpyrifos was associated with greater blood α-synuclein. We observed somewhat greater α-synuclein with the PON1-108T (lower paraoxonase enzyme) allele, and with ≥ 10 h of exposure to cholinesterase inhibiting insecticides in the preceding 30 days, but neither of these associations followed a clear dose-response pattern. These results suggest that selected genetic and environmental factors may affect α-synuclein blood levels. However, longitudinal studies with larger numbers of pesticide handlers will be required to confirm and elucidate the possible associations observed in this exploratory cross-sectional study.