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  • Introduction Trichloroacetic acid TCA might

    2020-04-17

    Introduction Trichloroacetic Guvacoline hydrobromide (TCA) might enhance the activation of T cells and disrupt various activities of peripheral T cells [1], which is related to human immune function and reduces human immunity. Trichloroethylene (TCE) has been widely used in many manufacturing industries [2], and it is a widespread water pollutant [3]. Although TCE is classified as carcinogenic to humans and is associated with kidney-specific toxicity [4,5], the toxicity study of TCA, a metabolite and a breakdown product of TCE, remains uncertain. In addition, TCA is a common organic contaminant of drinking water formed as by-products during chlorine disinfection. TCA could promote N-methyl-N-nitrosourea (MNU)-initiated foci of altered hepatocytes and induce the related liver tumors in B6C3F1 mice [5]. Moreover, it has reported that TCA could induce acute pulmonary injury and medicamentosa-like dermatitis due to the high concentration occupational exposure in Asia, especially in China [6,7]. Early-life environmental factors influences later-life susceptibility to cancer [8]. TCA has been testified to be nongenotoxic hepatocarcinogens since there is little evidence in vivo and vitro studies to indicate either genotoxic or mutagenic activity [9,10]. So there may exist a nongenotoxic mechanism in TCA induced tumors. TCA has been shown to increase cell proliferation and induced global DNA hypomethylation in mouse liver [11]. TCA has also been shown to up-regulate many protooncogenes, such as, H-ras, K-ras, Raf, C-fos, C-jun, IGF-II and C-myc, and lead to hypomethylation around the promoters of above genes [12]. Thus, epigenetic mechanisms play an important role in the toxic effect of TCA. However, the mechanism responsible for this chemical\'s hypomethylation and related biological effects remain unclear. In this study, we analyzed the impact of TCA on L-02 Cells. Previous studies have indicated that the decreased methylation status of DNA in TCA induced may be associated with the abnormal expression of DNA methyltransferases. This abnormal expression may play an important role in the process of TCA induced tumors, for malignant cells often exhibit abnormal expression of DNA methyltransferases. This epigenetic process acts as an alternative to mutations to disrupt the function of tumor suppressor gene and can predispose genetic alterations which often lead to malignant transformation. Epigenetic changes are heritable, metastable, and often reversible, which alters the way DNA-encoded information, but does not involve changes in DNA sequences [13]. The mechanism of DNA methylation has not been clearly defined. DNA methyltransferases catalyze the transfer of methyl groups to CpG dinucleotides residing in many possible sequence contexts to generate hemimethylated or fully methylated DNA. There are several different kinds of DNA methyltransferases, such as DNMT1, 2, 3a, 3b and DNMT3L. DNMT1 is believed to be the “maintenance” enzyme, maintains the methylation pattern during DNA replication [14], and involves in de novo DNA methylation [15]. The catalytic activity of the purified DNMT2 with DNA substrates is very low and almost undetectable in direct biochemical assays [16]. DNMT3a and DNMT3b are known as de novo methyltransferases and have preferred target sites, which are different from DNMT1 [17]. DNMT3L does not have similar catalytic domain of other DNA methyltransferases nor any methyltransferase activity [18]. DNMT1, DNMT3a and DNMT3b were selected to our study.
    Materials and methods
    Results
    Discussion TCA can induce the cell proliferation and prevention of apoptosis in mice [19]. However, Our study showed that TCA could not induce the cell proliferation directly, which might be associated with the complicated environment in vivo. TCA treated cells with 24 h recover course could significantly increase the S + G2 (M) phase, and this might be the evidence that TCA has the potential power to stimulate cell proliferation. A continuous exposure to TCA (0.9 mM 72 h) also had such trend. Therefore, TCA appears to enhance cell proliferation after its exposures in vitro. We found that exposure to TCA (≤0.9 mM) did not result in apoptosis of L-02 cells even for 72 h. Animal studies had the same result.