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Dieldrin augments mTOR signaling and inhibits lysosomal acidification in the adult zebrafish heart (Danio rerio).

Dieldrin augments mTOR signaling and inhibits lysosomal acidification in the adult zebrafish heart (Danio rerio).
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Slade L, Cowie A, Martynuik CJ, Kienesberger PC, Pulinilkunnil T,


Slade L, Cowie A, Martynuik CJ, Kienesberger PC, Pulinilkunnil T, (click to view)

Slade L, Cowie A, Martynuik CJ, Kienesberger PC, Pulinilkunnil T,

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The Journal of pharmacology and experimental therapeutics 2017 04 06() pii jpet.116.239806
Abstract

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 adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent, thus individuals may show latent adverse effects in the cardiovasculature system due to chronic, low dose exposure over time. Our objective was to determine whether low level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment, and show that dieldrin effects gene networks in the heart that are associated to the development of cardiovascular disease, specifically cardiac arrest and ventricular fibrillation. We report that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin while transcripts related to lysosomal function are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our results suggest that dieldrin constitutively activates Akt/mTOR signalling and downregulates lysosomal genes, participating in autophagy. Our data demonstrate that dieldrin induces genes associated with cardiovascular dysfunction and compromised lysosomal physiology, thereby identifying a novel mechanism for pesticide-induced diseases.

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