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Persistent increases in inflammatory cytokines, Akt, and MAPK/ERK pathways after inhalation exposure of rats to Libby amphibole (LA) or amosite: comparison to effects after intratracheal exposure to LA or naturally occurring asbestos.
Citation:
Gavett, S., D. Andrews, U. Kodavanti, AND J. Cyphert. Persistent increases in inflammatory cytokines, Akt, and MAPK/ERK pathways after inhalation exposure of rats to Libby amphibole (LA) or amosite: comparison to effects after intratracheal exposure to LA or naturally occurring asbestos. Society of Toxicology, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
The purpose of this study was to compare mechanisms of toxicity after exposure of rats to various types of asbestos by nose-only inhalation or intratracheal instillation. We also sought to compare responses after exposure to Libby amphibole to those after exposure to naturally occurring asbestos (NOA). Results show that persistent production of inflammatory cytokines and other pathway components may underlie toxicity of inhaled LA, while instilled LA had less persistent effects. Of the NOA samples tested, Sumas Mountain chrysotile (Region 10, Washington State) had toxicity similar to LA, which was greater than 2 other tested types.
Description:
Human exposure to LA and other mined or processed asbestos increases risk of lung inflammation, fibrosis, and cancer. Health risks from exposure to naturally occurring asbestos (NOA) are not as well-understood. Mechanisms of long-term toxicity were compared in male F344 rats exposed by nose-only inhalation (IH) or intratracheal (IT) instillation. Responses to IH LA (1.0, 3.3, or 10.0 mg/m3), amosite (AM; 3.3 mg/m3, as positive referent group), or air (all 6 hr/d, 5 d/wk, 13 wk) were evaluated 1 d, 1 mo, and 3 mo post-exposure. Responses to IT LA and NOA samples Sumas Mountain chrysotile (SM), El Dorado Hills tremolite (ED), and Ontario ferroactinolite (ON) (all at 0.5 or 1.5 mg/rat), or dispersion media (DM) only, were evaluated 1 d and 3 mo post-IT. Inflammatory cytokines, Akt, and MAPK/ERK pathway proteins were examined in lung tissue. Three mo after IH LA at 10.0 mg/m3, MAPK/ERK components (STAT3, MEK1/2) were significantly elevated 40-50% over air control. One day after IT LA or SM, STAT3, MEK1/2, and ERK1/2 were increased 2-5x over DM control. These IT effects were not present (MEK1/2, ERK1/2) or strongly attenuated (STAT3 for LA) at 3 mo post-exposure. Akt pathway components (S6RP, Akt) were increased 2x over air control 3 mo after 10.0 mg/m3 IH LA. One day post-IT, S6RP was increased 4x by 1.5 mg LA and 9x by 1.5 mg SM, and Akt was increased 2x by SM. By 3 mo post-IT, only Akt was significantly increased (2x by SM). TNF-alpha, IL-1beta, and CXCL1 were persistently increased 1 d to 3 mo after IH AM or LA. These targets were also increased 1 d post-IT LA and SM, but by 3 mo only CXCL1 and TNF-alpha remained elevated (for LA and ED). At 15 mo post-IT and 18 mo post-IH, LA promoted lung fibrosis and tumor development. We conclude that LA inhalation causes more persistent inflammation and activation of growth factor pathways than IT exposure, which may contribute to lung disease long after initial exposure. Pro-inflammatory effects of IT SM and LA were greater than those of ED and ON. (This abstract does not represent US EPA policy.)