Intratracheal exposure to multi-walled carbon nanotubes induces a nonalcoholic steatohepatitis-like phenotype in C57BL/6J mice

Abstract

The effects of multi-walled carbon nanotubes (MWCNTs) exposure have garnered great interest in the field of public health, due to the high aspect ratio of MWCNTs. Because of worldwide increases in obesity prevalence, nonalcoholic fatty liver disease (NAFLD) is now the most common prevalent liver disease and is considered to be a component of metabolic syndrome, which is a cluster of disorders that also includes dyslipidemia, diabetes mellitus, arteriosclerosis, and hypertension. Exposure to MWCNTs is known to be a risk factor for lung and cardiovascular diseases, but its effect on NAFLD is unknown. In this study, we investigated the effects of intratracheal exposure of two different types of MWCNTs, namely, pristine multi-walled carbon nanotubes (PMWCNTs) and acid-treated multi-walled carbon nanotubes (TMWCNTs), on liver pathogenesis. Direct instillation of a test material into the lungs has been employed as a quantitatively reliable alternative method of inhalation exposure. The 10% weight loss dose was assessed in three months of subchronic study and is defined here as the maximum tolerated dose (MTD) of PMWCNTs and TMWCNTs; by this metric, MTD for a 1-year exposure of MWCNTs was determined to be 0.1 mg/mouse. Mice exposed to PMWCNTs and TMWCNTs for one year developed a nonalcoholic steatohepatitis (NASH)-like phenotype, characterized by inflammation, hepatic steatosis, and fibrosis. Furthermore, PMWCNTs induced a more severe NASH-like phenotype than TMWCNTs, which was related to consistent up-regulation of interleukin (IL)-6 and plasminogen activator inhibitor (PAI)-1. Impaired cholesterol homeostasis, overexpression of NF-κBp65, and suppression of peroxisome proliferator-activated receptor gamma (PPARγ) in the liver were also observed.