SPLENIC TOXICITY OF ANILINE

Summary

Principal Investigator: M Firoze Khan
Abstract: Our long-term objective is to elucidate the mechanisms of the splenic toxicity of aromatic amines, and to develop preventive and therapeutic strategies. Using aniline as a prototypic compound, studies in our previous funding period demonstrated that aniline exposure in rats leads to oxidative stress in the spleen, evident from increases in reactive iron, lipid peroxidation, protein oxidation, DMA oxidation, lipid-derived aldehyde-protein adducts and nitrotyrosine. These changes are accompanied by activation of the transcription factors NF-kappaB and AP-1, and up-regulation of fibrogenic and inflammatory cytokines. Morphologically, spleen showed vascular congestion, increased red pulp cellularity due to increased sinusoidal cells and fibroblasts, capsular thickening and fibrosis. Having established the important role of oxidative stress in the splenic toxicity of aniline, we will now direct our studies toward the aniline-induced oxidative stress pathways that lead to splenic fibrosis and tumorigenesis. We hypothesize that aniline-induced oxidative stress due to over-production of oxidants (ROS and RNS) activates redox-sensitive transcription factors (NF-kappaB and AP-1) leading to transcription of genes involved in fibrosis and cell growth regulatory pathways in the spleen. Furthermore, oxidative damage to DNA leads to gene mutations. These events, individually or in concert, lead to fibrosis and/or tumorigenesis in the spleen. This hypothesis will be tested by pursuing three specific aims: Aim 1 will elucidate the regulation of transcription factors NF-kappaB and AP-1, signaling mechanisms and related gene expression in the splenic toxicity of aniline. Aim 2 will examine the role of oxidative DNA damage and repair, malondialdehyde-DNA adducts, DNA methylation, and mutations in the tumor suppressor gene p53 in aniline-induced splenic toxicity. Aim 3 will investigate the contribution of reactive nitrogen species to splenic damage by characterizing iNOS regulation and the formation of nitrated proteins, and by examining the role of NO/ONOO in the regulation of NF-kappaB activation, cytokine expression and DNA damage. These studies will elucidate the mechanisms of aniline-induced splenic toxicity, and will be important in devising strategies to prevent toxicity, and in risk assessment of aniline and other structurally-related aromatic amines.
Funding Period: ----------------1994 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Toxicol Appl Pharmacol 230:227-34. 2008
  2. pmc Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Toxicol Appl Pharmacol 233:247-53. 2008
  3. pmc Up-regulation of heme oxygenase-1 in rat spleen after aniline exposure
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Free Radic Biol Med 48:513-8. 2010
  4. pmc Induction of base excision repair enzymes NTH1 and APE1 in rat spleen following aniline exposure
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 267:276-83. 2013
  5. pmc Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 250:213-20. 2011
  6. pmc Induction of NEIL1 and NEIL2 DNA glycosylases in aniline-induced splenic toxicity
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 251:1-7. 2011
  7. pmc Aniline-induced nitrosative stress in rat spleen: proteomic identification of nitrated proteins
    Xiuzhen Fan
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 255:103-12. 2011

Detail Information

Publications7

  1. pmc Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Toxicol Appl Pharmacol 230:227-34. 2008
    ..The observed sequence of events following aniline exposure could initiate a fibrogenic and/or tumorigenic response in the spleen...
  2. pmc Oxidative DNA damage and its repair in rat spleen following subchronic exposure to aniline
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Toxicol Appl Pharmacol 233:247-53. 2008
    ..Accumulation of mutagenic oxidative DNA lesions in the spleen following exposure to aniline could play a critical role in the tumorigenic process...
  3. pmc Up-regulation of heme oxygenase-1 in rat spleen after aniline exposure
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 0438, USA
    Free Radic Biol Med 48:513-8. 2010
    The splenic toxicity of aniline is characterized by vascular congestion, hyperplasia, fibrosis, and the development of a variety of sarcomas in rats...
  4. pmc Induction of base excision repair enzymes NTH1 and APE1 in rat spleen following aniline exposure
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 267:276-83. 2013
    ..These findings thus identify a novel mechanism through which NTH1 and APE1 may regulate the repair of oxidative DNA damage in aniline-induced splenic toxicity...
  5. pmc Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen
    Jianling Wang
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 250:213-20. 2011
    ..Our data suggest that increased expression of cyclins, CDKs and phosphorylation of pRB protein could be critical in cell proliferation, and may contribute to aniline-induced tumorigenic response in the spleen...
  6. pmc Induction of NEIL1 and NEIL2 DNA glycosylases in aniline-induced splenic toxicity
    Huaxian Ma
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 251:1-7. 2011
    ....
  7. pmc Aniline-induced nitrosative stress in rat spleen: proteomic identification of nitrated proteins
    Xiuzhen Fan
    Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Toxicol Appl Pharmacol 255:103-12. 2011
    ....