Functional profiling discovers the dieldrin organochlorinated pesticide affects leucine availability in yeast

Area of Science:

• Environmental Toxicology
• Molecular Biology
• Cellular Biology

Background:

• Organochlorine pesticides like dieldrin are linked to serious health issues, including neurodegenerative diseases, endocrine disruption, and cancer.
• The precise cellular and molecular mechanisms underlying dieldrin's toxicity are not well understood.
• Understanding these mechanisms is crucial for assessing and mitigating health risks associated with pesticide exposure.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms of dieldrin toxicity using a functional genomics approach.
• To identify specific cellular pathways and genes affected by dieldrin exposure.
• To explore the role of amino acid metabolism, particularly leucine, in dieldrin's toxic effects.

Main Methods:

• Utilized the model eukaryote Saccharomyces cerevisiae for functional genomics studies.
• Assessed dieldrin sensitivity in various yeast mutants, including those defective in amino acid signaling and transport.
• Investigated the effects of exogenous leucine, gene overexpression, and dieldrin concentration on yeast growth and survival.
• Monitored leucine uptake and the induction of the amino acid starvation response.
• Examined the role of the Ras/protein kinase A pathway and the pyruvate dehydrogenase complex in dieldrin tolerance.

Main Results:

• Dieldrin exposure was found to alter leucine availability in yeast cells.
• Yeast mutants with defects in amino acid signaling or transport exhibited sensitivity to dieldrin, which was reversed by adding leucine.
• Dieldrin sensitivity was directly correlated with leucine concentration in the growth media.
• Overexpression of leucine-biosynthesis or transport proteins conferred resistance to dieldrin.
• Dieldrin inhibited leucine uptake and induced a cellular amino acid starvation response.
• Negative regulation of the Ras/protein kinase A pathway and an intact pyruvate dehydrogenase complex were essential for dieldrin tolerance.

Conclusions:

• Dieldrin toxicity is mediated, at least in part, by the disruption of leucine availability and the induction of amino acid starvation responses.
• The findings highlight the critical role of amino acid metabolism and specific signaling pathways in cellular defense against dieldrin.
• The identified yeast genes and pathways have human orthologs, suggesting potential relevance for understanding dieldrin toxicity in humans and informing public health strategies.