Expression of Xenobiotic Biomarkers CYP1 Family in Preputial Tissue of Patients with Hypospadias and Phimosis and Its Association with DNA Methylation Level of SRD5A2 Minimal Promoter.
Expression of Xenobiotic Biomarkers CYP1 Family in Preputial Tissue of Patients with Hypospadias and Phimosis and Its Association with DNA Methylation Level of SRD5A2 Minimal Promoter.
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DOI：
10.1007/s00244-017-0466-x
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发表时间：
2018-03
影响因子：
4
通讯作者：
Kojima Y
中科院分区：
文献类型：
--
作者：
Ohsako S;Aiba T;Miyado M;Fukami M;Ogata T;Hayashi Y;Mizuno K;Kojima Y
一些流行病学研究表明，由于胎儿阶段暴露于环境污染物，男性生殖器官畸形，包括尿道下裂或隐睾症的发病率有所增加。然而，化学品暴露与患者组织中靶调控基因表达的相关性尚未报道。由于人类研究中的实验方法或临床试验有限，特别是使用胎儿和/或婴儿的方法，因此很难获得男性生殖畸形机制的明确生理学证据。因此，缺乏生理学证据使得这个问题备受争议。我们分析了尿道下裂（n = 23）和包茎（n = 16）患者的包皮组织。非典型CYP 1家族基因CYP 1A 1和CYP 1B 1是环境化学暴露的潜在生物标志物。然后，我们通过定量RT-PCR分析比较了尿道下裂和包茎样本中CYP 1A 1和CYP 1B 1的表达水平。由于雄激素相关基因参与了男性生殖系统疾病的发病过程，因此还测定了SRD 5A 2和AR的mRNA表达水平。尿道下裂组中CYP 1B 1表达水平显著高于包茎组，而AR表达水平显著低于包茎组。尿道下裂患者中CYP 1家族mRNA表达水平与SRD 5A 2 mRNA表达水平呈正相关（P < 0.001），而包茎患者中CYP 1家族mRNA表达水平与SRD 5A 2 mRNA表达水平无相关性。此外，通过亚硫酸氢盐基因组测序确定四个基因的甲基化水平。尽管SRD 5A 2启动子区域显示中度甲基化，但在CYP 1A 1、CYP 1B 1或AR中未检测到甲基化。尿道下裂和包茎患者SRD 5A 2基因启动子甲基化水平无显著差异。在尿道下裂患者中，SRD 5A 2甲基化水平（尤其是在-221 Sp1位点）与CYP 1家族mRNA表达水平（CYP 1A 1，p = 0.002; CYP 1B 1，p = 0.007）之间存在负相关性，但在包茎患者中则不存在。包皮组织中SRD 5A 2基因的mRNA表达水平与CYP 1家族基因的mRNA表达水平呈显著正相关，甲基化水平与CYP 1家族基因的mRNA表达水平呈负相关，这似乎表明尿道下裂患者的化学暴露。本文的在线版本（doi：10.1007/s 00244 -017-0466-x）包含补充材料，可供授权用户使用。
Several epidemiological studies have suggested that the incidence of male reproductive organ malformations, including hypospadias or cryptorchidism, has increased due to fetal-stage exposure to environmental pollutants. However, the association of chemical exposure with the expression of target regulatory genes in the tissues of patients has not yet been reported. Because experimental approaches or clinical trials in human studies are limited, especially those using fetal and/or infants, it is difficult to obtain clear physiological evidence of mechanisms underlying male reproductive malformations. Thus, the lack of physiological evidence makes this issue controversial. We analyzed preputial tissues from patients with hypospadias (n = 23) and phimosis (n = 16). The atypical CYP1 family genes, CYP1A1 and CYP1B1, are potential biomarkers of environmental chemical exposure. We then compared the expression levels of CYP1A1 and CYP1B1 between hypospadias and phimosis samples by quantitative RT-PCR analysis. The mRNA expression levels of SRD5A2 and AR also were measured, because the androgen-related genes involved in the onset of disorders of male reproductive system. A significantly higher CYP1B1 expression level and a lower AR expression level were observed in the hypospadias groups than in the phimosis group. Positive correlations (P < 0.001) between the mRNA expression levels of the CYP1 family and SRD5A2 were found in patients with hypospadias but not in those with phimosis. Moreover, the methylation levels of the four genes were determined by bisulfite genomic sequencing. Although the SRD5A2 promoter region showed moderate methylation, no methylation was detected in CYP1A1, CYP1B1, or AR. There was no significant difference in SRD5A2 promoter methylation level between hypospadias and phimosis patients. Negative correlations were found between the methylation level of SRD5A2, especially at the − 221 Sp1 site, and the CYP1 family mRNA expression levels (CYP1A1, p = 0.002; CYP1B1, p = 0.007) in hypospadias patients, but not in phimosis patients. The significant positive association of mRNA expression level and the negative association of methylation level of the SRD5A2 gene with the mRNA expression levels of CYP1 family genes in the preputial tissue seem to indicate the chemical exposure of patients with hypospadias. The online version of this article (doi:10.1007/s00244-017-0466-x) contains supplementary material, which is available to authorized users.
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