The Modulation of Multi-walled Carbon Nanotube-induced Acute Lung Pathology by Mouse Strain, Glutathione Status, and Nanotube Characteristics
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Multi-walled carbon nanotubes (MWCNTs) are concentric cylinders of graphene with useful industrial properties and possible human toxicities due to their high aspect ratio, reactive surface chemistry, and respirable size. Worldwide manufacturing capacity of carbon nanotubes (CNTs) increased ten-fold from 2006 to 2011, reflecting manufacturing improvements and increased demand. However, this dramatic expansion has outpaced animal testing for toxicity—thereby presenting a potential occupational health hazard to workers at risk for inhaling MWCNTs during manufacturing and handling. While several human studies into the effects of occupational exposure have been published, current understanding of MWCNT-induced lung pathology largely derives from in vitro cell culture studies and in vivo animal studies. However, the literature frequently contradicts itself on the consequences of MWCNT introduction into the rodent lung: CNTs have been reported as highly inflammogenic, pro-fibrotic, damaging to cellular and lung barrier integrity, and capable of engendering severe oxidative stress. CNTs have also been reported as non-inflammogenic, non-fibrotic, non-cytotoxic, and capable of scavenging reactive oxygen species. These contradictions may derive from significant interlaboratory differences in MWCNT preparation and rodent exposures, as well as from the incredible diversity in physicochemical properties of various manufactured MWCNTs. These contradictory data impede effective risk assessments and regulations to reduce the risk of lung exposure in workers. Furthermore, the majority of studies only examined MWCNT-induced pathology in a narrow selection of rodent strains, predominantly the C57BL/6 mouse. This narrow approach likely fails to capture important variations in genetic susceptibility to lung pathology within a workforce growing 14% annually in the United States. To improve understanding of the associations between MWCNT-induced lung inflammation and specific physicochemical characteristics, along with genetic differences in susceptibility, I have developed the following aims: Aim 1: To elucidate which physicochemical characteristics of nine well-characterized MWCNTs are associated with acute lung inflammation in A/J mice. Aim 2: To determine if there is a differential response to MWCNT-induced acute lung inflammation across ten isogenic mouse strains. Aim 3: To investigate how a genetically-induced deficiency in the cellular antioxidant glutathione modulates susceptibility to MWCNT-induced acute lung inflammation in a gender-dependent manner in C57BL/6 mice.
- Environmental health