Our long-term goal is to elucidate the mechanisms of splenic toxicity resulting from exposure to aromatic amines, and to develop preventive/therapeutic strategies. We use the industrial chemical aniline as a prototypic amine. Besides causing methemoglobinemia, hemolysis and hemolytic anemia, aniline exposure also results in selective splenic toxicity. The mechanism(s) for this selective splenic damage are not well understood. Studies in our previous funding period demonstrated that aniline exposure increased iron content, lipid peroxidation, protein oxidation and lipid-derived aldehyde-protein adducts (markers of oxidative stress) in rat spleens. These events are accompanied by such morphological changes as vascular congestion, increased sinusoids and fibroblasts, erythrophagocytocysis, capsular thickening and fibrosis. We hypothesize that aniline toxicity is caused by oxidative stress, and postulate the following sequence of events leading to splenic toxicity: Aniline (and/or its metabolites) damage erythrocytes, which are deposited in the spleen, and so increase total and reactive iron (free iron). This iron overload generates oxidants (probably hydroxyl radicals), causing oxidative stress leading to cellular dysfunction and fibrosis [increased collagen synthesis mediated by fibrogenic cytokines and activation of transcription factors)]. This hypothesized sequence of events will be tested by pursuing three specific aims:
Aim 1 identify the oxidizing species and iron species that mediate aniline toxicity.
Aim 2 will characterize the oxidized biomolecules in the spleens of aniline-exposed rats, especially the lipid peroxidation products and their protein and DNA adducts; the oxidized proteins will also be characterized.
Aim 3 will examine how the induction of fibrogenic cytokines; activation of stress-induced transcription factor(s), and collagen synthesis contribute to aniline toxicity. Our project will elucidate the mechanism(s) of aniline-induced splenic toxicity, and will define the roles of oxidative stress, aldehyde products of lipid peroxidation, fibrogenic cytokines and transcription factor(s) in this process. Understanding the mechanism(s) of aniline toxicity will be very important in developing novel preventive and therapeutic strategies for aromatic amines, in general.
| Wang, Jianling; Wang, Gangduo; Khan, M Firoze (2015) Disorder of G2-M Checkpoint Control in Aniline-Induced Cell Proliferation in Rat Spleen. PLoS One 10:e0131457 |
| Ma, Huaxian; Wang, Jianling; Abdel-Rahman, Sherif Z et al. (2013) Induction of base excision repair enzymes NTH1 and APE1 in rat spleen following aniline exposure. Toxicol Appl Pharmacol 267:276-83 |
| Wang, Jianling; Wang, Gangduo; Ma, Huaxian et al. (2011) Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen. Toxicol Appl Pharmacol 250:213-20 |
| Fan, Xiuzhen; Wang, Jianling; Soman, Kizhake V et al. (2011) Aniline-induced nitrosative stress in rat spleen: proteomic identification of nitrated proteins. Toxicol Appl Pharmacol 255:103-12 |
| Ma, Huaxian; Wang, Jianling; Abdel-Rahman, Sherif Z et al. (2011) Induction of NEIL1 and NEIL2 DNA glycosylases in aniline-induced splenic toxicity. Toxicol Appl Pharmacol 251:1-7 |
| Wang, Jianling; Ma, Huaxian; Boor, Paul J et al. (2010) Up-regulation of heme oxygenase-1 in rat spleen after aniline exposure. Free Radic Biol Med 48:513-8 |
| Ma, Huaxian; Wang, Jianling; Abdel-Rahman, Sherif Z et al. (2008) Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline. Toxicol Appl Pharmacol 233:247-53 |
| Wang, Jianling; Wang, Gangduo; Ansari, G A S et al. (2008) Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline. Toxicol Appl Pharmacol 230:227-34 |
