Abstract
BackgroundPrenatal environmental conditions may influence disease risk in later life. We previously found a gene-environment interaction between the paraoxonase 1 (PON1) Q192R genotype and prenatal pesticide exposure leading to an adverse cardio-metabolic risk profile at school age. However, the molecular mechanisms involved have not yet been resolved. It was hypothesized that epigenetics might be involved. The aim of the present study was therefore to investigate whether DNA methylation patterns in blood cells were related to prenatal pesticide exposure level, PON1 Q192R genotype, and associated metabolic effects observed in the children.MethodsWhole blood DNA methylation patterns in 48 children (6–11 years of age), whose mothers were occupationally unexposed or exposed to pesticides early in pregnancy, were determined by Illumina 450 K methylation arrays.ResultsA specific methylation profile was observed in prenatally pesticide exposed children carrying the PON1 192R-allele. Differentially methylated genes were enriched in several neuroendocrine signaling pathways including dopamine-DARPP32 feedback (appetite, reward pathways), corticotrophin releasing hormone signaling, nNOS, neuregulin signaling, mTOR signaling, and type II diabetes mellitus signaling. Furthermore, we were able to identify possible candidate genes which mediated the associations between pesticide exposure and increased leptin level, body fat percentage, and difference in BMI Z score between birth and school age.ConclusionsDNA methylation may be an underlying mechanism explaining an adverse cardio-metabolic health profile in children carrying the PON1 192R-allele and prenatally exposed to pesticides.
Highlights
Prenatal environmental conditions may influence disease risk in later life
A common polymorphism in the coding sequence of the paraoxonase 1 (PON1) gene substitutes glutamine (Q) to arginine (R) at position 192. This substitution seems to affect both properties of the enzyme, and several studies have indicated an increased risk of cardiovascular disease in R-allele carriers [17, 18]. To investigate if this polymorphism affected the sensitivity to prenatal pesticide exposure, the PON1 Q192R genotype was determined in the children
In accordance with the findings for the whole cohort [19], birth weights were significantly lower and measures of body composition, increase in BMI Z score from birth to school age, diastolic blood pressure, and leptin and insulin concentrations at school age were significantly higher in the exposed PON1 192QR/RR group compared with the unexposed QR/ RR group
Summary
Prenatal environmental conditions may influence disease risk in later life. We previously found a geneenvironment interaction between the paraoxonase 1 (PON1) Q192R genotype and prenatal pesticide exposure leading to an adverse cardio-metabolic risk profile at school age. A common polymorphism in the coding sequence of the PON1 gene substitutes glutamine (Q) to arginine (R) at position 192 This substitution seems to affect both properties of the enzyme, and several studies have indicated an increased risk of cardiovascular disease in R-allele carriers [17, 18]. To investigate if this polymorphism affected the sensitivity to prenatal pesticide exposure, the PON1 Q192R genotype was determined in the children. The obtained results indicate a gene-environment interaction between pesticide exposure and PON1 gene heterogeneities already in early prenatal life that might enhance the risk of cardio-metabolic diseases later in life
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