Genome-wide Gene Expression Changes Associated With Exposure of Rat Liver, Heart, and Kidney Cells to Endosulfan

Toxicol In Vitro. 2018 Apr;48:244-254. doi: 10.1016/j.tiv.2018.01.022. Epub 2018 Jan 31.

Abstract

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death.

Keywords: Cytotoxicity; Endosulfan; Extracellular matrix-receptor interaction; Hypoxia-inducible factor-1; RNA-seq.

MeSH terms

  • Animals
  • Cell Line
  • Endosulfan / toxicity*
  • Extracellular Matrix / drug effects
  • Gene Expression / drug effects*
  • Genome-Wide Association Study
  • Hepatocytes / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
  • Insecticides / toxicity*
  • Kidney / cytology*
  • Kidney / drug effects*
  • Myocytes, Cardiac / drug effects*
  • Primary Cell Culture
  • Rats
  • Signal Transduction / drug effects

Substances

  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insecticides
  • Endosulfan