Activation of transcription factor AP-1 and mitogen-activated protein kinases in aniline-induced splenic toxicity

Khan, M. Firoze; Kannan, Subburaj; Wang, Jianling

doi:10.1016/j.taap.2005.08.006

Cited by 32 publications

(57 citation statements)

References 37 publications

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“…Freshly isolated splenocytes were used for the nuclear protein extraction (Wang et al, 2005;Khan et al, 2006). Nuclear protein extracts (10 µg) from control or aniline-treated splenocytes were incubated with an oligonucleotide containing the NF-κB or p-c-Jun consensus binding site bound to 96-well microtiter plate.…”

Section: Quantitation Of Nf-κb and Ap-1 Activation In The Splenocytesmentioning

confidence: 99%

“…After blocking with non-fat dry milk (5%, w/v), the membrane was incubated with antibodies specific for NF-κB p65, p-NF-κB p65, c-Jun and pc-Jun (Cell signaling). The rest of the procedures were the same as described below for MAPK Western blot analysis (Khan et al, 2006).…”

Section: Western Blot Analysis For Nf-κb and Ap-1mentioning

confidence: 99%

“…In fact, aniline-induced splenic toxicity could be largely attributed to iron overload (increases in both total and free iron) as iron-induced oxidative and nitrosative stress in the spleen causes increased lipid peroxidation, protein oxidation, DNA oxidation and nitrotyrosine formation (Khan et al, 1997a(Khan et al, , 1997b(Khan et al, , 1999a(Khan et al, , 2003b(Khan et al, , 2003cWu et al, 2005). Earlier subchronic aniline exposure studies (related to fibrogenic response in the spleen) have also shown activation of redoxsensitive transcription factors (TFs) nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) in the spleen (Wang et al, 2005;Khan et al, 2006). However, status of these TFs and the possible mechanisms in their activation, especially the upstream signaling pathways, and consequences of their activation (downstream target genes) at an early stage which precedes fibrosis in the spleen are not known.…”

Section: Introductionmentioning

confidence: 99%

“…A variety of agents which are known to generate ROS, have also been shown to regulate AP-1 activation (Hsu et al, 2000;Klaunig and Kamendulis, 2004;Khan et al, 2006). AP-1 consists of a family of Jun/Fos dimers that include different Jun proteins (c-Jun, JunB, and JunD) and Fos proteins (c-Fos, FosB, Fra-1, Fra-2, and FosB2) (Angel and Karin, 1991).…”

Section: Introductionmentioning

confidence: 99%

“…AP-1 consists of a family of Jun/Fos dimers that include different Jun proteins (c-Jun, JunB, and JunD) and Fos proteins (c-Fos, FosB, Fra-1, Fra-2, and FosB2) (Angel and Karin, 1991). AP-1 activation could be regulated by the activation of MAPKs, involving three major pathways of extracellular signal-related kinases (ERKs), stress-activated protein kinases/c-jun NH 2 -terminal kinases (JNKs) and p38 MAPK (Hsu et al, 2000;Khan et al, 2006). We hypothesize that anilineinduced oxidative stress in the spleen leads to phosphorylation of IKK and MAPKs, resulting in the activation of TFs NF-κB and AP-1 leading to up-regulation of cytokine gene expression in the spleen, and thus causing toxicity.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Ansari

et al. 2008

Toxicology and Applied Pharmacology

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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 anilineinduced 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 (1 mmol/kg/day via gavage) for 7 days, an experimental condition that precedes the appearance of fibrosis. Significant increases in both NF-κB 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-IκBα, p-p65 and p-c-Jun. To understand the upstream signaling events which could account for the activation of NF-κB and AP-1, phosphorylation patterns of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) were pursued. Our data showed remarkable increases in both p-IKKα and p-IKKβ in the splenocytes from aniline-treated rats, suggesting their role in the phosphorylation of both IκBα and p65 subunits. Furthermore, aniline exposure led to activation of all three classes of MAPKs, as evident from increased phosphorylation of extracellularsignal-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-κB. Activation of upstream signaling molecules was also associated with simultaneous increases in gene transcription of cytokines IL-1, IL-6 and TNF-α. The observed sequence of events following aniline exposure could initiate a fibrogenic and/or tumorigenic response in the spleen.

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Section: Quantitation Of Nf-κb and Ap-1 Activation In The Splenocytesmentioning

confidence: 99%

Section: Western Blot Analysis For Nf-κb and Ap-1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

Ansari

et al. 2008

Toxicology and Applied Pharmacology

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Anilin [MAK Value Documentation in German language, 2018]

Hartwig¹,

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated the maximum concentration at the workplace (MAK value) for aniline [62-53-3]. Available publications and unpublished study reports are described in detail. Healthy male and female volunteers showed increased methemoglobin values in a 6-hour-inhalation-study with exposure to 2 ml aniline/m 3. The median methemoglobin augmentation was 0.5 % from the base level of 0.7 % to 1.2 % methemoglobin. Even taking into account the highest observed increase of methemoglobin, 8 hour-exposure time and the increased respiratory volume at the workplace, a methemoglobin value of more than 5 % would not be expected. Based on this, the MAK value for aniline of 2 ml/m 3 (7.7 mg/m 3) is confirmed. Aniline is still assigned to Peak Limitation Category II, because systemic effects are critical and the excursion factor of 2 is confirmed. Skin contact is expected to contribute significantly to the systemic toxicity. Therefore, the designation with an "H" is confirmed. Aniline continues to be designated with "Sh" and assigned to Carcinogenicity Category 4.

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Aniline [MAK Value Documentation, 2018]

Hartwig

Arand²

2019

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the workplace (MAK value) for aniline [ 62‐53‐3 ]. Available publications and unpublished study reports are described in detail. Healthy male and female volunteers showed increased methaemoglobin values in a 6‐hour‐inhalation‐study with exposure to 2 ml aniline/m 3 . The median methaemoglobin augmentation was 0.5% from the base level of 0.7% to 1.2% methaemoglobin. Even taking into account the highest observed increase of methaemoglobin, 8 hour‐exposure time and the increased respiratory volume at the workplace, a methaemoglobin value of more than 5% would not be expected. Based on this, the MAK value for aniline of 2 ml/m 3 (7.7 mg/m 3 ) is confirmed. Aniline is still assigned to Peak Limitation Category II, because systemic effects are critical and the excursion factor of 2 is confirmed. Skin contact is expected to contribute significantly to the systemic toxicity. Therefore, the designation with an “H” is confirmed. Aniline continues to be designated with “Sh” and assigned to Carcinogenicity Category 4.

show abstract

Activation of transcription factor AP-1 and mitogen-activated protein kinases in aniline-induced splenic toxicity

Cited by 32 publications

References 37 publications

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

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

Anilin [MAK Value Documentation in German language, 2018]

Aniline [MAK Value Documentation, 2018]

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