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    • DNA methylation is a kind

    2022-06-27

    DNA methylation is a kind of epigenetic modifications that can be described as a heritable alteration in gene expression, without any changes in the DNA sequence. Recent evidences suggest that the regulation of DNA methylation status is a frequent and early event in prostate carcinogenesis. For example, Glutathione S-transferase P1 (GSTP1), a biomarker for prostate cancer, is commonly down-regulated in prostate tumor progression and is correlated with the DNA methylation status (Singal et al., 2001). The promoter region of the estrogen receptor 2 (ESR2) gene is hypermethylated in prostate cancer tissues, which inactivate its effect as a tumor suppressor (Nojima et al., 2001). Yegnasubramanian et al. have further demonstrated that a panel of aberrantly hypermethylated genes including GSTP1, APC, PTGS2, MDR1 and Rassf1a are unique to PCa as compared to other cancers, and even correlated with disease stage (Yegnasubramanian et al., 2004). In the present study, we determine to investigate whether early life exposure of DEHP could induce epigenetic and transcriptional changes of carcinogenesis-related genes and whether those changes during early life could contribute to the susceptibility of prostate carcinoma in a long term. Among numbers of carcinogenesis-related genes, we selected 6 genes involved in differentiation and growth of prostate (NKX3.1), hormonal response (ESR2), signal transduction and cell growth regulation (PSCA), tumor suppression (GSTP1), inflammatory signaling (PTGS2), and Cy7.5 NHS ester (non-sulfonated) control (Rassf1a). In order to explore whether the early-life specific epigenetic modifications could mediate the effect of DEHP exposure on prostate carcinogenesis in rodents, we assessed the effect of DEHP exposure on DNA methylation and mRNA expression of these genes on PND 21 in F1 male rats, and evaluated their relationship with prostate carcinogenesis parameters on PND 196.
    Materials and methods
    Results
    Discussion Increasing evidence suggests that maternal endocrine disrupting chemicals exposure could alter epigenome of the offspring and lead to disease pathogenesis later in life (Alavian-Ghavanini and Ruegg, 2018). The results reported by Martinez-Arguelles et al. further supported it by indicating that exposure of DEHP phthalate early in life could induces epigenetic changes that maybe linked to altered gene expression and function in the adult, even if the toxicant is discontinued from use (Martinez-Arguelles and Papadopoulos, 2015). In the current study, the gene expression and methylation during the critical developmental period of prostate were determined to explore whether epigenetic changes could mediate the carcinogenesis effect of DEHP. Based on rat models, IUL exposure to DEHP was found to increase the mRNA expression of GSTP1, PTGS2 and PSCA in early life, which were significantly associated to the pre-neoplastic lesions of the prostate gland as the animal aged. Our data further showed that IUL exposures to DEHP could alter DNA methylation of PSCA gene, and it may be a predisposing factor for prostate carcinogenesis in adulthood. Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that is associated with malignant progression of pre-malignant prostate lesions and advanced clinical stage and metastasis of prostate cancer (Gu et al., 2000). In this study, we found that developmental DEHP exposure resulted in an epigenetic modification of PSCA in prostate. Once CpG methylation pattern was established in somatic cells, it would remain stable and heritable via cell divisions with aging, which suggested a regulation mechanism involved in the high expression of PSCA in prostate during the fetal and neonatal period. Interestingly, previous studies have found that elevation of PSCA could either mediate the proliferation and cell cycle progression of PCa cells in vitro via PI3K/AKT pathway or promote PCa growth and metastasis through P38/NF-κB/IL-6 signaling pathways (Li et al., 2017; Liu et al., 2017). In this regard, high expression of PSCA induced by IUL exposure to DEHP might be a promising early developmental event that predisposes the prostate to neoplasia with aging. Indeed, we found the expression of PSCA in critical period of prostate development to be positively related to the PIN scores (reflecting precursor lesion of prostate carcinogenesis), Gleason scores (reflecting pathological stage of prostate carcinogenesis), and serum PSA concentrations (predictor of prostate cancer-specific mortality) later in life. These results were consistent with studies revealing that higher PSCA expression was related with high-grade PIN, and tightly linked to the prostate carcinogenesis (Zhao et al., 2009; Zhigang and Wenlu, 2007, Zhigang and Wenlu, 2008).