Stress response pathways protect germ cells from omega-6 polyunsaturated fatty acid-mediated toxicity in Caenorhabditis elegans

Abstract

Polyunsaturated fatty acids serve both structural and functional roles as membrane components and precursors for a number of different factors involved in inflammation and signaling. These fatty acids are required in the human diet, although excess dietary intake of omega-6 fatty polyunsaturated fatty acids may have a negative influence on human health. In the model nematode, Caenorhabditis elegans, dietary exposure to dihomo- gamma-linolenic acid (DGLA), an omega-6 fatty acid, causes the destruction of germ cells and leads to sterility. In this study we used genetic and microscopic approaches to further characterize this phenomenon. We found that strains carrying mutations in genes involved in lipid homeostasis enhanced sterility phenotypes, while mutations reducing the activity of the conserved insulin/IGF signaling pathway suppressed sterility phenotypes. Exposure to a mild heat stress prior to omega-6 fatty acid treatment led to an adaptive or hormetic response, resulting in less sterility. Mutations in skn-1 and knockdown of genes encoding phase II detoxification enzymes led to increased sterility in the presence of dietary DGLA. Thus, detoxification systems and genetic changes that increase overall stress responses protect the germ cells from destruction. Microscopic analyses revealed that dietary DGLA leads to deterioration of germ cell membranes in the proliferative and transition zones of the developing germ line. Together, these data demonstrate that specific omega-6 polyunsaturated fatty acids, or molecules derived from them, are transported to the germ line where they disrupt the rapidly expanding germ cell membranes, leading to germ cell death.

Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans

“…Our finding that only ARA and EPA can suppress Asdf suggests that specific species of eicosanoids could be responsible for the physiological responses that we observed. C20 PUFAs also play a critical role in maintaining membrane fluidity (42), and thus the addition of these C20 PUFAs could alter membrane function and signaling capacity; however, the opposing responses to DGLA compared with ARA and EPA suggest that this is not simply a general disorganization of the lipid bilayer (43). Nevertheless, future assessment of the phospholipid composition of membranes, the signaling pathways that influence Asdf, and the functional consequences of perturbing these components on Asdf capacity and resulting phenotypes will be of great interest.…”

Polyunsaturated fatty acid derived signaling in reproduction and development: Insights from Caenorhabditis elegans and Drosophila melanogaster

“…Exposing developing larvae to DGLA during the critical period of mitotic expansion of germ cells (L2–L3 larval stages) leads to complete sterility in adults, even when they are removed from DGLA exposure during the last larval stage (Watts and Browse, 2006). Adult exposure to DGLA leads to destruction of germ cells in the mitotic and meiotic transition region (Webster et al, 2013). These studies were carried out using hermaphrodite C. elegans , which are anatomically female, but produce sperm for a short period before oogenesis commences so that they can undergo self-fertilization.…”

“…Strains carrying mutations in the nuclear hormone receptor genes nhr-80 and nhr-49 , which regulate the expression of fatty acid desaturases and other lipid synthesis and degradation enzymes, are extremely sensitive to DGLA and become sterile when exposed to DGLA at levels that have no effect in wild-type (Webster et al, 2013). Conversely, long-lived mutants defective in insulin signaling, such as daf-2 , which are resistant to many environmental stressors, show impressive resistance to DGLA (Webster et al, 2013). Thus, the process of DGLA-induced sterility is very sensitive to genetic manipulation.…”

Dietary Supplementation of Polyunsaturated Fatty Acids in <em>Caenorhabditis elegans</em>

“…Interestingly, the response to DGLA can be altered by genetic mutations in C. elegans. A recent finding is that the insulin growth factor-dependent stress pathways can suppress the DGLA-induced germ cell destruction 8 . Supplementing the diet of worms containing deleterious mutations in either the daf-2 insulin/IGF receptor, daf-2(e1370), or the daf-16/FOXO transcription factor, daf-16(mu86), illustrates the usefulness of this method to unravel genetic pathways that influence the physiological effects of dietary fats.…”

“…C. elegans ingest the PUFA-containing bacteria, and this dietary supplementation is sufficient to rescue the defects of PUFAdeficient mutants. Supplementation of most fatty acids has no detrimental effects on wild type animals, however, specific omega-6 fatty acids, especially dihomo-gamma linolenic acid (DGLA, 20:3n-6) cause a permanent destruction of C. elegans germ cells 7,8 .…”