|
| Status |
Public on Jul 23, 2019 |
| Title |
Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
|
| Summary |
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 midbrains were dissected. DNA was isolated and dieldrin-related changes in DNA methylation were assessed via reduced representation bisulfite sequencing (RRBS). We identified significant, sex-specific differentially methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin exposure (FDR<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. Furthermore, a separate set of changes in DNA methylation was identified after adult exposure to dieldrin, suggesting that adult and developmental dieldrin toxicity may not act through a shared epigenetic mechanism. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to additional environmental stimuli and contribute to the development of late-life neurodegenerative disease, including PD.
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| Overall design |
RRBS data for developmental exposure: control (n=12; male n=6, female n=6) vs. dieldrin treatment (0.3 mg/kg) (n=12; male n=6, female n=6). RNA-seq data for developmental exposure: control (n=12; male n=6, female n=6) vs. dieldrin treatment (0.3 mg/kg) (n=12; male n=6, female n=6). RRBS data for adult exposure: control (n=5; only male) vs. dieldrin treatment (0.3 mg/kg) (n=5; only male).
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| Contributor(s) |
Kochmanski J, VanOeveren SE, Bernstein AI |
| Citation(s) |
30859219 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R21 ES029205 |
Dieldrin exposure and synucleinopathy |
MICHIGAN STATE UNIVERSITY |
Alison Bernstein |
| R00 ES024570 |
Epigenetic effects of adult and developmental exposure to Parkinsonian toxicants |
MICHIGAN STATE UNIVERSITY |
Alison Bernstein |
|
| Submission date |
Jul 22, 2019 |
| Last update date |
Jul 25, 2019 |
| Contact name |
Alison I Bernstein |
| E-mail(s) |
bernst79@msu.edu
|
| Phone |
6162340957
|
| Organization name |
Michigan State University
|
| Department |
Translational Neuroscience
|
| Lab |
Bernstein Lab
|
| Street address |
400 Monroe Ave NW
|
| City |
Grand Rapids |
| State/province |
MI |
| ZIP/Postal code |
49503 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (58)
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| Relations |
| BioProject |
PRJNA555989 |
| SRA |
SRP215922 |
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