Abstract
Hexavalent chromium [Cr(IV)], a well-known industrial waste product and an environmental pollutant, is recognized as a human carcinogen. But its mechanisms of carcinogenicity remain unclear, and recent studies suggest that DNA methylation may play an important role in the carcinogenesis of Cr(IV). The aim of our study was to investigate the effects of Cr(IV) on cell cycle progress, global DNA methylation, and DNA methylation of p16 gene. A human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5–15 µM potassium dichromate or 1.25–5 µg/cm2 lead chromate for 2–24 hours. Cell cycle was arrested at G1 phase by both compounds in 24 hours exposure group, but global hypomethylation occurred earlier than cell cycle arrest, and the hypomethylation status maintained for more than 20 hours. The mRNA expression of p16 was significantly up-regulated by Cr(IV), especially by potassium dichromate, and the mRNA expression of cyclin-dependent kinases (CDK4 and CDK6) was significantly down-regulated. But protein expression analysis showed very little change of p16 gene. Both qualitative and quantitative results showed that DNA methylation status of p16 remained unchanged. Collectively, our data suggested that global hypomethylation was possibly responsible for Cr(IV) - induced G1 phase arrest,but DNA methylation might not be related to up-regulation of p16 gene by Cr(IV).
Highlights
Chromium (Cr) and its compounds are widely used in many industries such as chromate manufacturing, chrome plating, ferrochrome production and stainless steel welding
Our results showed that significant (P,0.05) increase of p16 protein expression levels was only observed in human B lymphoblastoid cells exposed to 15 mM of K2Cr2O7 and in A549 cells exposed to 5.0 mg/cm2 of PbCrO4
Aberrant DNA methylation is believed to be associated with various diseases and developmental disabilities such as cancer and mental retardation, and global hypomethylation and sitespecific hypermethylation are common features of human tumors [17,18,19]
Summary
Chromium (Cr) and its compounds are widely used in many industries such as chromate manufacturing, chrome plating, ferrochrome production and stainless steel welding. Chromium can be found in the environment in the form of airborne particles from automobile catalytic converters. Hexavalent chromium [Cr (VI)] is one of two major forms of Cr, and it is recognized as a human carcinogen. It is estimated that tens of millions of people are exposed to chromium worldwide [1]. There are three well-accepted general carcinogenic paradigms which include multistage carcinogenesis, genomic instability and epigenetic modifications [3]. Since epigenetics was first introduced by Conrad Waddington in 1942, people are paying more and more attention to it, which plays a significant role in phenotypic expression. Global DNA hypomethylation is generally associated with chromosomal instability, and hypermethylation at promoter of specific gene may silence the expression of this gene [6]
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