Molecular Mechanism of Aniline Induced Spleen Toxicity and Neuron Toxicity in Experimental Rat Exposure: A Review

Abstract

Aniline exposure leads to neuron and spleen toxicity specifically and makes diverse neurological effects and sarcoma that is defined by splenomegaly, hyperplasia, and fibrosis and tumors formation at the end. However, the molecular mechanism(s) of aniline-induced spleen toxicity is not understood well, previous studies have represented that aniline exposure results in iron overload and initiation of oxidative/nitrosative disorder stress and oxidative damage to proteins, lipids and DNA subsequently, in the spleen. Elevated expression of cyclins, cyclin-dependent kinases (CDKs) and phosphorylation of pRB protein along with increases in A, B and CDK1 as a cell cycle regulatory proteins cyclins, and reduce in CDK inhibitors (p21 and p27) could be critical in cell cycle regulation, which contributes to tumorigenic response after aniline exposure. Aniline-induced splenic toxicity is correlated to oxidative DNA damage and initiation of DNA glycosylases expression (OGG1, NEIL1/2, NTH1, APE1 and PNK) for removal of oxidative DNA lesions in rat. Oxidative stress causes transcriptional up-regulation of fibrogenic/inflammatory factors (cytokines, IL- 1, IL-6 and TNF-α) via induction of nuclear factor-kappa B, AP-1 and redox-sensitive transcription factors, in aniline treated-rats. The upstream signalling events as phosphorylation of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) could potentially be the causes of activation of NF-κB and AP-1. All of these events could initiate a fibrogenic and/or tumorigenic response in the spleen. The spleen toxicity of aniline is studied more and the different mechanisms are suggested. This review summarizes those events following aniline exposure that induce spleen toxicity and neurotoxicity.

Keywords: Aniline; neurology; neurotoxicity; oxidative stress; pharmacology; spleen toxicity..

Fig. (1)

Schematic diagram depicting proposed mechanisms responsible for aniline inducedspleen toxicity. Aniline exerts its toxicity through labile iron accumulation and induction of oxidative/nitrosative stress. As depicted, oxidative damage to proteins, lipids and DNA by ROS/RNS can initiate many signaling pathway. ROS/RNS also induce fibrogenic and pro-inflammatory mediators. These phenomena together with other changes result in spleen toxicity. (The color version of the figure is available in the electronic copy of the article).

Fig. (2)

Induction of signal transduction cascades and activation of transcription factors AP-1 and NF-B. Two major pathways, the NF-B (right) and the MAPK pathway (left) are activated by ROS after aniline exposure. Excessive reactive oxygen species (ROS) derived from iron accumulation activate MAPKs and IKK. Activated IKK phosphorylates IκB and leads to ubiquitination and proteasome degradation of IκB, releasing NF-κB proteins, such as p50 and p65. Activated MAPKs in other hand, activate AP-1. The free p50 and p65 and Jun/ Fos dimers translocate into nuclei and regulate transcription of a variety of genes including TNF, IL-1, IL-6 that finally induce inflammatory and fibrosis responses. (The color version of the figure is available in the electronic copy of the article).

Fig. (3)

Photomicrographs of the thoracic spinal cord of rats after single injection of aniline at 4 weeks of age and post-treatment day 15. (a) Severe spongy change in the white matter in rat after 1,000 mg/kg injection of aniline. HE. × 50. (b) Vacuoles in the the white matter of rat after 750 mg/kg injection of aniline. HE. × 70 [17].