The role of autophagy in environmental toxicants-induced dermatitis and toxicity

  • 李 宥萱

Student thesis: Doctoral Thesis

Abstract

Autophagy serves as a defense strategy when facing environmental stress in several organisms This conserved physiological process plays a pivotal role in the regulation of homeostasis and also cell survival/death and inflammatory responses The increasing evidence that various environmental toxicants such as heavy metals and nanoparticles (NPs) lead to autophagy and cellular damage suggests that the influence of the environment on an organism at the molecular level represent a key variable in several diseases Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease Hexavalent chromium (Cr (VI)) can activate the Akt NF-κB and MAPK pathways and induce cell death via the effects of reactive oxygen species (ROS) In addition to causing chromium hypersensitivity high ROS levels are indicative of oxidative stress and also contributed to NPs toxicity More and more studies have recently reported that heavy metals and nanomaterials can induce autophagy but the mechanisms by which autophagy regulates hypersensitivity and nanotoxicity remains unclear In the present study we investigated : (1) The relationship among ROS autophagy and Cr(VI)-induced hypersensitivity and (2) the nanoparticle toxicity bio-indicators and possible mechanisms of different size silver nanoparticles (AgNPs)-induced cytotoxicity in the NIH3T3 cell line First of all the induction of apoptosis autophagy and ROS were observed after different concentrations of Cr(VI) treatment HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy which could affect cell viability In addition Cr(VI) activated the Akt NF-κB and MAPK pathways and thereby increasing IL-1? and TNF-? production All of these stimulation phenomena were inhibited by NAC in both in vitro and in vivo studies These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting ROS-induced cell death and cytokine expression Secondary AgNPs were taken up by NIH 3T3 cells and localized within the intracellular endosomal compartments Smaller AgNPs (SAS) were more toxic than larger AgNPs (LAS) Our results suggest that SAS leads to more lysosomal swelling arrested autophagic flux and cell death The mechanisms underlying the AgNPs-induced autophagy in cells could be mediated by the activation of oxidative stress and endoplasmic reticulum (ER) stress signaling pathways AgNPs treatment can trigger the expression of ER stress and autophagy markers (IRE1and LC3-II) However the autophagy substrate p62 accumulated in AgNPs-treated cells indicating that the autophagy process was inhibited Thus autophagy activation may be a key player in the cellular response against nano-toxicity Taken together these works illustrate the influence of autophagy on biological systems and demonstrate the study of autophagy is pivotal in the development of hypersensitivity and new approaches for toxicological studies
Date of Award2015 Jul 28
Original languageEnglish
SupervisorYing-Jan Wang (Supervisor)

Cite this

The role of autophagy in environmental toxicants-induced dermatitis and toxicity
宥萱, 李. (Author). 2015 Jul 28

Student thesis: Doctoral Thesis