Genetic Pathways Involved in Omega-6 Fatty Acid-Induced Sterility in C. elegans

Christopher Michael Webster

Polyunsaturated fatty acids serve both structural and functional roles as membrane components as well as precursors for a number of different factors involved in inflammation and signaling. Humans are unable to synthesize the full range of biologically active polyunsaturated fatty acids, requiring them to be present in the diet. While polyunsaturated fatty acids in the diet are required, the optimal ratio of dietary omega–6 to omega–3 polyunsaturated fatty acids has not been determined, even though this ratio appears to influence many aspects of human health. We used the model organism C. elegans to better understand the biological effects of altered ratios of dietary polyunsaturated fatty acids. Unlike mammals, C. elegans can synthesize all of the unsaturated fatty acids needed for biological function. Interestingly, dietary exposure to a specific omega–6 fatty acid, dihomo–γ–linolenic acid, causes germ cell loss and sterility. We took a genetic approach to identify both enhancers and suppressors of the sterility response induced through dietary supplementation of omega–6 polyunsaturated fatty acids in C. elegans. We found that genetic manipulation of the highly conserved Insulin/IGF signaling pathway, along with other stress response pathways, affects dihomo–γ–linolenic acid induced sterility. RNAi knockdown of detoxification enzymes resulted in significant enhancement of the sterility phenotypes suggesting that a toxic lipophilic mediator contributes to the sterility response. Exposure to a mild heat stress prior to omega–6 fatty acid treatment led to an adaptive or hormetic response, resulting in increased resistance. Using adult worms with a normal germline, we observed a reduction in the proliferative germ line pool after a short period of dihomo–γ–linolenic acid feeding. Microscopic analyses demonstrated that the proliferative mitotic germ cells undergo membrane disruption upon exposure to dihomo–γ–linolenic acid. Furthermore, irreversible sterility occurs during feeding experiments in larval stage worms possessing only a small pool of proliferative germ cells. Together this data indicate that specific omega–6 polyunsaturated fatty acids, or molecules derived from them, target and kill progenitor germ cells. The data presented here contribute to growing knowledge of the function and biological activity of omega–6 polyunsaturated fatty acids.

Genetic Pathways Involved in Omega-6 Fatty Acid-Induced Sterility in C. elegans

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