Intergenerational Inheritance of Altered Metabolism Phenotypes After Early‐life Stress in Caenorhabditis elegans

Abstract

Environmental stress experienced during critical periods of animal development has been shown to impact adult phenotypes through changes in behavior or physiology. In humans, undernutrition in utero can lead to obesity and metabolic disorders in adulthood that can be inherited for two generations in the absence of the original stress. However, how particular stresses can result in tissue‐specific changes in target gene expression, and how that gene expression can be inherited, is not well understood. We have established Caenorhabditis elegans nematodes as a model system to investigate the molecular mechanisms that regulate environmental programming of gene expression. C. elegans larvae experiencing early‐life stress (starvation or crowding) may enter the stress resistant, developmentally arrested dauer stage. When environmental conditions improve, larvae will exit dauer and proceed with reproductive development (postdauers, PD). In previous work, we have shown using RNA‐Seq that hermaphrodites that experienced starvation‐induced dauer (PDStv) exhibited significant changes in gene expression compared to continuously fed animals (control, CON), most notably a downregulation of germline‐expressed genes and upregulation of genes with functions in fatty acid metabolism. These changes in gene expression correlated with production of fewer progeny and a decrease in stored intestinal lipids by Oil Red O (ORO) staining in PDStv adults compared to controls. The observed reduction in fecundity in PDStv hermaphrodites was dependent on functional Δ9‐desaturase genes, fat‐5, fat‐6, and fat‐7,as well as the DAF‐12/VDR steroid signaling pathway, indicating a connection between the starvation‐induced metabolism changes and fertility. Interestingly, embryos of PDStv hermaphrodites contained significantly more lipids compared to control embryos, suggesting that PDStv adults prioritize lipid production for reproduction rather than somatic maintenance after dauer exit. We next examined the lipid storage F1 and F2 generation adults using ORO staining, and found that F1 progeny of PDStv adults have significantly increased lipid storage compared to controls. This difference in lipid storage is reset in the F2 generation. Additionally, inheritance of the altered metabolism in F1 adults is dependent upon PRG‐1/PIWI and HRDE‐1/AGO siRNA pathways. In recent work, we are further investigating the connection between metabolism and fecundity of an animal that experienced early‐life stress. We examined the progeny number of PDStv adults that were cultivated on E. coli OP50 supplemented with different fatty acid molecules. We observed that supplementation with oleic acid (OA) resulted in a significant increase in progeny number compared to animals fed only E. coli, while other fatty acids resulted in no change or a decrease in progeny number. Furthermore, the OA‐dependent increase in progeny number required the Δ9‐desaturase FAT‐7, as well as the DAF‐12/VDR steroid signaling pathway, suggesting that OA may be modifying the starvation‐induced phenotypes of PDStv adults. Together, these results suggest that OA may be acting as a signaling molecule to modulate reproductive plasticity through regulation of the DAF‐12/VDR steroid signaling pathway in response to environmental conditions.