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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 — an exploratory   study

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.


Genomic location of sig-DMPs. DMPs were mapped to gene elements (top left), CpG islands (top right), and chromatin state segmentations (bottom). Asterisks indicate significant enrichment or depletion in comparison with all Illumina probes (gray bars) measured by the Fisher’s exact test (P value < 0.05). Sig–DMPs where the interaction term was significant (blue bars) showed an enrichment in promoter regions and CpG islands. Sig-DMPs where no interaction was seen (orange bars) showed no significant enrichment or depletion in a particular genomic region
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Fig4: Genomic location of sig-DMPs. DMPs were mapped to gene elements (top left), CpG islands (top right), and chromatin state segmentations (bottom). Asterisks indicate significant enrichment or depletion in comparison with all Illumina probes (gray bars) measured by the Fisher’s exact test (P value < 0.05). Sig–DMPs where the interaction term was significant (blue bars) showed an enrichment in promoter regions and CpG islands. Sig-DMPs where no interaction was seen (orange bars) showed no significant enrichment or depletion in a particular genomic region

Mentions: Next, we questioned whether the sig-DMPs were enriched or depleted in a specific genomic location (Fig. 4). Sig-DMPs for which interaction between exposure and PON1 Q192R genotype was seen, were enriched in promoter regions (200 and 1500 bp upstream of transcription start sites) and depleted in gene bodies, 3′UTRs and intergenic regions. This was also evident when we overlapped the sig-DMPs with different chromatin states, where we observed enrichment in active and poised promoters, while DMPs were depleted in regions like transcriptional elongation, weak transcribed, and heterochromatin regions. Furthermore, DMPs were significantly more located in CpG islands and less observed in CpG poor regions. Sig-DMPs found in the models without an interaction term were not enriched or depleted in a particular genomic region.Fig. 4


Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk — an exploratory   study
Genomic location of sig-DMPs. DMPs were mapped to gene elements (top left), CpG islands (top right), and chromatin state segmentations (bottom). Asterisks indicate significant enrichment or depletion in comparison with all Illumina probes (gray bars) measured by the Fisher’s exact test (P value < 0.05). Sig–DMPs where the interaction term was significant (blue bars) showed an enrichment in promoter regions and CpG islands. Sig-DMPs where no interaction was seen (orange bars) showed no significant enrichment or depletion in a particular genomic region
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Genomic location of sig-DMPs. DMPs were mapped to gene elements (top left), CpG islands (top right), and chromatin state segmentations (bottom). Asterisks indicate significant enrichment or depletion in comparison with all Illumina probes (gray bars) measured by the Fisher’s exact test (P value < 0.05). Sig–DMPs where the interaction term was significant (blue bars) showed an enrichment in promoter regions and CpG islands. Sig-DMPs where no interaction was seen (orange bars) showed no significant enrichment or depletion in a particular genomic region
Mentions: Next, we questioned whether the sig-DMPs were enriched or depleted in a specific genomic location (Fig. 4). Sig-DMPs for which interaction between exposure and PON1 Q192R genotype was seen, were enriched in promoter regions (200 and 1500 bp upstream of transcription start sites) and depleted in gene bodies, 3′UTRs and intergenic regions. This was also evident when we overlapped the sig-DMPs with different chromatin states, where we observed enrichment in active and poised promoters, while DMPs were depleted in regions like transcriptional elongation, weak transcribed, and heterochromatin regions. Furthermore, DMPs were significantly more located in CpG islands and less observed in CpG poor regions. Sig-DMPs found in the models without an interaction term were not enriched or depleted in a particular genomic region.Fig. 4

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&ndash;11&nbsp;years of age), whose mothers were occupationally unexposed or exposed to pesticides early in pregnancy, were determined by Illumina 450&nbsp;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.