Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline

Journal Article · Tue Jul 15 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.02.022· OSTI ID:21140897

Jianling, Wang; Gangduo, Wang; Ansari, G A.S. ^[1]

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1. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0438 (United States)

Aniline exposure causes toxicity to the spleen, which leads to a variety of sarcomas, and fibrosis appears to be an important preneoplastic lesion. However, early molecular mechanisms in aniline-induced toxicity to the spleen are not known. Previously, we have shown that aniline exposure results in iron overload and induction of oxidative stress in the spleen, which can cause transcriptional upregulation of fibrogenic/inflammatory cytokines via activation of oxidative stress (OS)-responsive signaling pathways. To test this mechanism, male SD rats were treated with aniline (1mmol/kg/day via gavage) for 7days, an experimental condition that precedes the appearance of fibrosis. Significant increases in both NF-{kappa}B and AP-1 binding activity was observed in the nuclear extracts of splenocytes from aniline-treated rats as determined by ELISAs, and supported by Western blot data showing increases in p-I{kappa}B{alpha}, p-p65 and p-c-Jun. To understand the upstream signaling events which could account for the activation of NF-{kappa}B and AP-1, phosphorylation patterns of I{kappa}B kinases (IKK{alpha} and IKK{beta}) and mitogen-activated protein kinases (MAPKs) were pursued. Our data showed remarkable increases in both p-IKK{alpha} and p-IKK{beta} in the splenocytes from aniline-treated rats, suggesting their role in the phosphorylation of both I{kappa}B{alpha} and p65 subunits. Furthermore, aniline exposure led to activation of all three classes of MAPKs, as evident from increased phosphorylation of extracellular-signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK1/2) and p38 MAPKs, which could potentially contribute to the observed activation of both AP-1 and NF-{kappa}B. Activation of upstream signaling molecules was also associated with simultaneous increases in gene transcription of cytokines IL-1, IL-6 and TNF-{alpha}. The observed sequence of events following aniline exposure could initiate a fibrogenic and/or tumorigenic response in the spleen.

• OSTI ID: 21140897
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 230; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANILINE
ENZYME IMMUNOASSAY
FIBROSIS
GENES
INFLAMMATION
IRON
LYMPHOKINES
OXIDATION
PHOSPHORYLATION
PHOSPHOTRANSFERASES
RATS
SARCOMAS
SPLEEN
TOXICITY
TRANSCRIPTION