title: Evaluation of the hepatotoxic risk caused by lead acetate via skin exposure using a proteomic approach.
abstract: Lead compounds exhibit a high degree of cytotoxicity and carcinogenicity. We evaluated the impact of lead acetate on the liver by skin exposure as well as the changes in protein profiles reflecting pathogenic processes. Functional proteomic tools showed that the most meaningful protein changes were involved in protein folding, ER stress, and apoptosis in the presence of an organic lead compound. Treatment with lead acetate also elicits intracellular ROS levels as well as carbonyl modification of chaperone proteins, suggesting that lead might trigger the unfolded protein response due to oxidative stress. Lead application induced ER stress, as indicated by the promotion of GRP78 and by increased expression of the transcription factors ATF6, IRE1α, and PERK. Moreover, upregulation of GRP75 may participate in lead-caused hepatic cytotoxicity while abrogation of GRP75 appears to attenuate the inhibition of cell growth. Our findings demonstrate that accumulation of organic lead in the liver can induce oxidative imbalance and protein impairment that may result in ER stress followed by liver injuries. Hepatic proteome profiles delineate a finer picture of protein networks and metabolic pathways primarily involved in lead-initiated hepatic toxicity via skin exposure.
authors.affiliation: Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.forename: Chun-Hsun
authors.initials: CH
authors.lastname: Huang
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Hung
authors.forename: Tai-Long
authors.initials: TL
authors.lastname: Pan
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D050050:Protein Carbonylation / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D040901:Proteomics; D012867:Skin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009942:Organometallic Compounds; D011506:Proteins; C008261:lead acetate
keywords: Animal proteomics; Chaperone; Functional proteome; Hepatic toxicity; Lead acetate; Oxidative stress