Abstract
Aniline, a toxic aromatic amine, is known to cause hemopoietic toxicity both in humans and animals. Aniline exposure also leads to toxic response in spleen which is characterized by splenomegaly, hyperplasia, fibrosis and the eventual formation of tumors on chronic in vivo exposure. Previously, we have shown that aniline exposure leads to iron overload, oxidative DNA damage, and increased cell proliferation, which could eventually contribute to a tumorigenic response in the spleen. Despite our demonstration that cell proliferation was associated with deregulation of G1 phase cyclins and increased expression of G1 phase cyclin-dependent kinases (CDKs), molecular mechanisms, especially the regulation of G2 phase and contribution of epigenetic mechanisms in aniline-induced splenic cellular proliferation remain largely unclear. This study therefore, mainly focused on the regulation of G2 phase in an animal model preceding a tumorigenic response. Male Sprague-Dawley rats were given aniline (0.5 mmol/kg/day) in drinking water or drinking water only (controls) for 30 days, and expression of G2 phase cyclins, CDK1, CDK inhibitors and miRNAs were measured in the spleen. Aniline treatment resulted in significant increases in cell cycle regulatory proteins, including cyclins A, B and CDK1, particularly phosphor-CDK1, and decreases in CDK inhibitors p21 and p27, which could promote the splenocytes to go through G2/M transition. Our data also showed upregulation of tumor markers Trx-1 and Ref-1 in rats treated with aniline. More importantly, we observed lower expression of miRNAs including Let-7a, miR-15b, miR24, miR-100 and miR-125, and greater expression of CDK inhibitor regulatory miRNAs such as miR-181a, miR-221 and miR-222 in the spleens of aniline-treated animals. Our findings suggest that significant increases in the expression of cyclins, CDK1 and aberrant regulation of miRNAs could lead to an accelerated G2/M transition of the splenocytes, and potentially to a tumorigenic response on chronic aniline exposure.
Highlights
The precise causes of cancer are still not known, but the environmental factors including environmental and occupational carcinogenic chemical exposure play a potential role in the etiology of cancer [1,2]
To further unravel the molecular mechanisms of aniline-mediated cell proliferation, the current study focused on assessing the expression of cell cycle proteins and genes, especially Gap 2 (G2) phase cyclins, CDK1, cyclin-dependent kinases (CDKs) inhibitors and miRNAs in an animal model preceding a tumorigenic response following aniline exposure
CDK1-cyclin A complex remains into late G2 phase until replaced by CDK1-cyclin B complex and is implicated in activation and stabilization of CDK1-cyclin B which is responsible for driving cells through mitosis [34,35,36]
Summary
The precise causes of cancer are still not known, but the environmental factors including environmental and occupational carcinogenic chemical exposure play a potential role in the etiology of cancer [1,2]. A widely used industrial chemical, has been implicated in splenic toxicity including splenomegaly, hyperplasia, fibrosis, and a variety of sarcomas on chronic exposure in rats [3,4,5,6,7,8]. Our recent studies have shown iron overload and oxidative stress with consequent increase in oxidative DNA damage and cellular proliferation in the spleen of rats following aniline exposure. Such events could potentially lead to a mutagenic and/or carcinogenic response in the spleen [15,16,17]
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