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Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk ‚ÄĒ an exploratory ¬† study

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ABSTRACT

Background: Prenatal 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.

Methods: Whole 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.

Results: A 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.

Conclusions: DNA 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-017-0336-4) contains supplementary material, which is available to authorized users.

No MeSH data available.


Association between PON1 activity and PON1 methylation. The P values of the main effect for methylation are displayed using the linear model PON1 activity‚ÄČ~‚ÄČM value‚ÄČ+‚ÄČPON1-192 genotype‚ÄČ+‚ÄČsex. Red colored samples are PON1 192 R-allele carriers, and samples in blue are children with the PON1 192QQ genotype
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Fig6: Association between PON1 activity and PON1 methylation. The P values of the main effect for methylation are displayed using the linear model PON1 activity‚ÄČ~‚ÄČM value‚ÄČ+‚ÄČPON1-192 genotype‚ÄČ+‚ÄČsex. Red colored samples are PON1 192 R-allele carriers, and samples in blue are children with the PON1 192QQ genotype

Mentions: Beside the genome-wide DNA methylation effects of the PON1 Q192R genotype, we also observed a wide variation in DNA methylation in the PON1 promoter itself for nine Illumina cg-probes. Prenatal pesticide exposure and/or PON1 Q192R genotype did not affect PON1 promoter methylation status. However, another polymorphism (rs705379, PON1 -108CT) in the promoter region of PON1 could explain a large extent of this variation (Fig. 5). Individuals homozygous for the T-allele showed higher methylation values compared with the homozygous C-allele carriers. As expected, heterozygous individuals had an intermediate methylation value. Furthermore, the paraoxonase 1 activity was significantly associated with DNA methylation in the PON1 promoter region, with higher methylation values resulting in lower paraoxonase 1 activity (Fig. 6). PON1 Q192R genotype had the strongest effect on PON1 activity, while variation in PON1 promoter methylation led to a smaller but significant effect on PON1 activity.Fig. 5


Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk ‚ÄĒ an exploratory ¬† study
Association between PON1 activity and PON1 methylation. The P values of the main effect for methylation are displayed using the linear model PON1 activity‚ÄČ~‚ÄČM value‚ÄČ+‚ÄČPON1-192 genotype‚ÄČ+‚ÄČsex. Red colored samples are PON1 192 R-allele carriers, and samples in blue are children with the PON1 192QQ genotype
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5382380&req=5

Fig6: Association between PON1 activity and PON1 methylation. The P values of the main effect for methylation are displayed using the linear model PON1 activity‚ÄČ~‚ÄČM value‚ÄČ+‚ÄČPON1-192 genotype‚ÄČ+‚ÄČsex. Red colored samples are PON1 192 R-allele carriers, and samples in blue are children with the PON1 192QQ genotype
Mentions: Beside the genome-wide DNA methylation effects of the PON1 Q192R genotype, we also observed a wide variation in DNA methylation in the PON1 promoter itself for nine Illumina cg-probes. Prenatal pesticide exposure and/or PON1 Q192R genotype did not affect PON1 promoter methylation status. However, another polymorphism (rs705379, PON1 -108CT) in the promoter region of PON1 could explain a large extent of this variation (Fig. 5). Individuals homozygous for the T-allele showed higher methylation values compared with the homozygous C-allele carriers. As expected, heterozygous individuals had an intermediate methylation value. Furthermore, the paraoxonase 1 activity was significantly associated with DNA methylation in the PON1 promoter region, with higher methylation values resulting in lower paraoxonase 1 activity (Fig. 6). PON1 Q192R genotype had the strongest effect on PON1 activity, while variation in PON1 promoter methylation led to a smaller but significant effect on PON1 activity.Fig. 5

View Article: PubMed Central - PubMed

ABSTRACT

Background: Prenatal 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.

Methods: Whole 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.

Results: A 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.

Conclusions: DNA 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-017-0336-4) contains supplementary material, which is available to authorized users.

No MeSH data available.