Methylmercury exposure increases lipocalin related (lpr) and decreases activated in blocked unfolded protein response (abu) genes and specific miRNAs in Caenorhabditis elegans

Abstract

Methylmercury (MeHg) is a persistent environmental and dietary contaminant that causes serious adverse developmental and physiologic effects at multiple cellular levels. In order to understand more fully the consequences of MeHg exposure at the molecular level, we profiled gene and miRNA transcripts from the model organism Caenorhabditis elegans. Animals were exposed to MeHg (10µM) from embryo to larval 4 (L4) stage and RNAs were isolated. RNA-seq analysis on the Illumina platform revealed 541 genes up- and 261 genes down-regulated at a cutoff of 2-fold change and false discovery rate-corrected significance q < 0.05. Among the up-regulated genes were those previously shown to increase under oxidative stress conditions including hsp-16.11 (2.5-fold), gst-35 (10.1-fold), and fmo-2(58.5-fold). In addition, we observed up-regulation of 6 out of 7 lipocalin related (lpr) family genes and down regulation of 7 out of 15 activated in blocked unfolded protein response (abu) genes. Gene Ontology enrichment analysis highlighted the effect of genes related to development and organism growth. miRNA-seq analysis revealed 6–8 fold down regulation of mir-37-3p, mir-41-5p, mir-70-3p, and mir-75-3p. Our results demonstrate the effects of MeHg on specific transcripts encoding proteins in oxidative stress responses and in ER stress pathways. Pending confirmation of these transcript changes at protein levels, their association and dissocation characteristics with interaction partners, and integration of these signals, these findings indicate broad and dynamic mechanisms by which MeHg exerts its harmful effects.

RNA‐Seq Reveals Acute Manganese Exposure Increases Endoplasmic Reticulum Related and Lipocalin mRNAs in Caenorhabditis elegans

“…Interestingly, we also find upregulation of lpr family genes and downregulation of abu family genes in a previous study of methylmercury exposure . We also found a small number of FKB family members to be regulated by methylmercury ( fkb‐4 , 4.6 fold; fkb‐7 , 6.0 fold), although ant family genes were not significantly changed . These results suggest that there may be common pathways in heavy metal toxicity.…”

“…Although the protein function is not clear, LPR-5 provides an intriguing target for future studies to investigate Mn-induced toxicity mechanisms. Interestingly, we also find upregulation of lpr family genes and downregulation of abu family genes in a previous study of methylmercury ex-posure [20]. We also found a small number of FKB family members to be regulated by methylmercury (fkb-4, 4.6 fold; fkb-7, 6.0 fold), although ant family genes were not significantly changed [20].…”

“…The most over represented downregulated genes were genes involved in protein modification (155), meiosis (56), and mitosis (24). A significant amount of genes are also associated with DNA repair (20).…”

The putative multidrug resistance proteinMRP‐7 inhibits methylmercury‐associated animal toxicity and dopaminergic neurodegeneration inCaenorhabditis elegans

“…; Rudgalvyte et al . ). In order to determine if the expression of MRP‐7 may modulate MeHg‐associated cellular stress, particularly in specific intracellular compartments, we evaluated gene expression levels of several GSTs and HSPs following both acute and chronic toxicant exposures in both WT and mrp‐7 genetic knockdown animals.…”

“…MRP-7 expression reduces MeHg-associated endoplasmic reticulum, mitochondria, and Golgi apparatus stress response Exposure to MeHg has been shown to increase cellular reactive oxygen species and stress response gene expression Rudgalvyte et al 2013). In order to determine if the expression of MRP-7 may modulate MeHgassociated cellular stress, particularly in specific intracellular compartments, we evaluated gene expression levels of several GSTs and HSPs following both acute and chronic toxicant exposures in both WT and mrp-7 genetic knockdown animals.…”