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Developmental origins of Parkinson’s disease risk: developmental exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

ABSTRACT: Developmental origins of Parkinson’s disease risk: developmental exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

PROVIDER: PRJNA1101082 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28709600_1.fastq.gz	Fastqsanger.gz
	SRR28709600_2.fastq.gz	Fastqsanger.gz
	SRR28709601_1.fastq.gz	Fastqsanger.gz
	SRR28709601_2.fastq.gz	Fastqsanger.gz
	SRR28709602_1.fastq.gz	Fastqsanger.gz

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Project description:Rationale: Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiological studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been addressed adequately to date. This is a significant knowledge gap because these chemicals are detectable in human serum and are environmentally persistent, thus individuals may show latent adverse effects due to chronic, low dose exposure over time. Objective: To determine whether low level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Methods and Results: Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment, and show that dieldrin effects gene regulator networks in the heart that are associated with protein degradation. Our results show that genes related to the development of cardiovascular disease, specifically cardiac arrest and ventricular fibrillation, are affected by environmentally relevant levels of dieldrin. We find that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin treatments. Transcripts related to lysosomal function, also important to heart function, are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our data suggest that dieldrin constitutively activates Akt/mTOR signalling and downregulates lysosomal genes, which is hypothesized to be mediated through Transcription Factor EB (TFEB), the master regulator of lysosome function. Conclusions: This study is one of few to report that dieldrin alters molecular signaling cascades in the cardiovascular system and proposes a novel mechanism for pesticide-induced cardiotoxicity.

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Developmental origins of Parkinson’s disease risk: developmental exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

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