Bissegger Sonja, Martyniuk Christopher J, Langlois Valérie S
Chemistry and Chemical Engineering Department, Royal Military College of Canada, Kingston, ON, Canada.
Department of Biology and the Canadian River Institute, University of New Brunswick, NB, Canada.
Gen Comp Endocrinol. 2014 Jul 1;203:137-45. doi: 10.1016/j.ygcen.2014.01.018. Epub 2014 Feb 11.
Investigations of endocrine disrupting chemicals found in aquatic ecosystems with estrogenic and androgenic modes of action have increased over the past two decades due to a surge of evidence of adverse effects in wildlife. Chemicals that disrupt androgen signalling and steroidogenesis can result in an imbalanced conversion of testosterone (T) into 17β-estradiol (E2) and other androgens such as 5α-dihydrotestosterone (5α-DHT). Therefore, a better understanding of how chemicals perturb these pathways is warranted. In this study, the brain, liver, and testes of Silurana tropicalis were exposed ex vivo to the human drug finasteride, a potent steroid 5α-reductase inhibitor and a model compound to study the inhibition of the conversion of T into 5α-DHT. These experiments were conducted (1) to determine organ specific changes in sex steroid production after treatment, and (2) to elucidate the transcriptomic response to finasteride in testicular tissue. Enzyme-linked immunosorbent assays were used to measure hormone levels in media following finasteride incubation for 6 h. Finasteride significantly increased T levels in the media of liver and testis tissue, but did not induce any changes in E2 and 5α-DHT production. Gene expression analysis was performed in frog testes and data revealed that finasteride treatment significantly altered 1,434 gene probes. Gene networks associated with male reproduction such as meiosis, hormone biosynthesis, sperm entry, gonadotropin releasing hormone were affected by finasteride exposure as well as other pathways such as oxysterol synthesis, apoptosis, and epigenetic regulation. For example, this study suggests that the mode of action by which finasteride induces cellular damage in testicular tissue as reported by others, is via oxidative stress in testes. This data also suggests that 5-reductase inhibition disrupts the expression of genes related to reproduction. It is proposed that androgen-disrupting chemicals may mediate their action via 5-reductases and that the effects of environmental pollutants are not limited to the androgen receptor signalling.
在过去二十年中，由于野生动物出现不良影响的证据激增，对具有雌激素和雄激素作用模式的水生生态系统中发现的内分泌干扰化学物质的研究有所增加。干扰雄激素信号传导和类固醇生成的化学物质会导致睾酮（T）向17β-雌二醇（E2）和其他雄激素（如5α-二氢睾酮（5α-DHT））的转化失衡。因此，有必要更好地了解化学物质如何干扰这些途径。在本研究中，将热带爪蟾的脑、肝和睾丸离体暴露于人类药物非那雄胺，这是一种有效的类固醇5α-还原酶抑制剂，也是一种用于研究T转化为5α-DHT抑制作用的模型化合物。进行这些实验的目的是：（1）确定处理后性类固醇产生的器官特异性变化；（2）阐明睾丸组织对非那雄胺的转录组反应。使用酶联免疫吸附测定法测量非那雄胺孵育6小时后培养基中的激素水平。非那雄胺显著提高了肝和睾丸组织培养基中的T水平，但未引起E2和5α-DHT产生的任何变化。在青蛙睾丸中进行了基因表达分析，数据显示非那雄胺处理显著改变了1434个基因探针。与雄性生殖相关的基因网络，如减数分裂、激素生物合成、精子进入、促性腺激素释放激素，以及其他途径，如氧甾醇合成、细胞凋亡和表观遗传调控，都受到非那雄胺暴露的影响。例如，本研究表明，如其他人所报道的，非那雄胺在睾丸组织中诱导细胞损伤的作用方式是通过睾丸中的氧化应激。该数据还表明，5-还原酶抑制会破坏与生殖相关基因的表达。有人提出，破坏雄激素的化学物质可能通过5-还原酶介导其作用，并且环境污染物的影响不限于雄激素受体信号传导。
