Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson's Disease in Mouse Midbrain.
DNA methylation
Parkinson’s disease
RNA-sequencing
dieldrin
epigenetics
pesticides
Journal
Toxicological sciences : an official journal of the Society of Toxicology
ISSN: 1096-0929
Titre abrégé: Toxicol Sci
Pays: United States
ID NLM: 9805461
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
pubmed:
13
3
2019
medline:
6
5
2020
entrez:
13
3
2019
Statut:
ppublish
Résumé
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Despite previous work showing a link between developmental dieldrin exposure and increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, the mechanism mediating this effect has not been identified. Here, we tested the hypothesis that developmental exposure to dieldrin increases neuronal susceptibility via genome-wide changes in DNA methylation. Starting at 8 weeks of age and prior to mating, female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin by feeding (every 3 days) throughout breeding, gestation, and lactation. At 12 weeks of age, pups were sacrificed and ventral mesencephalon, containing primarily substantia nigra, was microdissected. DNA was isolated and dieldrin-related changes in DNA methylation were assessed via reduced representation bisulfite sequencing. We identified significant, sex-specific differentially methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin exposure (false discovery rate < 0.05), including DMCs at the Nr4a2 and Lmx1b genes, which are involved in dopaminergic neuron development and maintenance. Developmental dieldrin exposure had distinct effects on the male and female epigenome. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to subsequent toxic stimuli and contribute to the development of late-life neurodegenerative disease, including PD.
Identifiants
pubmed: 30859219
pii: 5374767
doi: 10.1093/toxsci/kfz069
pmc: PMC6542339
doi:
Substances chimiques
Grb10 protein, mouse
0
GRB10 Adaptor Protein
151441-47-3
Dieldrin
I0246D2ZS0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
593-607Subventions
Organisme : NIEHS NIH HHS
ID : R00 ES024570
Pays : United States
Organisme : NIEHS NIH HHS
ID : R21 ES029205
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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