Identification of Molecular Biomarkers in Rat Sperm and Testis Exposed to BPA

暴露于 BPA 的大鼠精子和睾丸中分子生物标志物的鉴定

• 批准号: 8478105
• 负责人: KIM BOEKELHEIDE
• 金额: $ 25.63万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478105
• 关键词: Address; Affect; Animals; Apoptotic; Biological Markers; Cells; Cues; Cytosine; DNA; DNA Methylation; Data; Development; Dose; Elderly; Endocrine Disruptors; Epidemiologic Studies; Epidemiology; Epigenetic Process; Estradiol; Ethinyl Estradiol; Functional disorder; Gene Expression; Gene Expression Profile; Generations; Genomics; Germ Cells; Germ Lines; Goals; Head; Human; Incidence; Injury; Instruction; Investigation; Left; Male Genital Organs; Measures; Messenger RNA; MicroRNAs; Modification; Molecular; Molecular Profiling; Occupational Exposure; Parents; Pattern; Physiological; Population; Rattus; Residual state; Rodent; Rodent Model; Seminal fluid; Seminiferous tubule structure; Signal Transduction; Spermatids; Spermatogenesis; Spermiogenesis; Staging; Staining and Labeling; Techniques; Testing; Testis; Tissues; Toxic effect; Transcript; Vertebral column; Work; base; bisphenol A; cell type; design; epigenetic marker; epigenomics; genome wide methylation; genome-wide; high throughput screening; imprint; in utero; insight; life history; male; men; methylome; reproductive; sex; sperm cell; spermatogenic epithelium structure; toxicant; translational study; zygote

Bisphenol A (BPA) is an endocrine disrupting chemical causing ubiquitous exposures in the developed world. Both animal studies and recent epidemiological evidence indicate that BPA targets the male reproductive tracl<, producing testicular injury and alterations in sperm parameters. Standard GLP-based approaches in rodent models have been relatively insensitive in detecting BPAinduced abnormalities in the male reproductive tract. We propose the use of well-established morphometric assessments ofthe testis, including quantitation of retained spermatid heads and the incidence of TUNELpositive germ cells, to enhance the sensitivity of detecting testicular effects of BPA exposure. In addition, we will identify molecular biomarkers of effect in the testis and sperm, by examining global mRNA and miRNA levels and genome-wide DNA methylation. Measuring these molecular biomarkers in sperm is expected to be particularly sensitive and specific, since sperm are an homogeneous population of cells that developed throughout their life history within the seminiferous epithelium. The GLP design provides multiple doses, and a positive estradiol control, allowing robust testing for the presence of a BPA-induced effect. In addition, we will assess both the paternal FO rats and their progeny, addressing differences across generations. The goal of this project is to test the following working hypothesis: addition ofthe enhanced morphological and molecular endpoints with the GLP design will provide more sensitive and specific biomarkers of BPA-induced male reproductive toxicity. The GLP study will be enhanced by morphometric assessments and molecular biomarkers of effects through the following Specific Aims: Specific Aim #1: will enhance the assessment of BPA-induced testicular injury using advanced histological and morphometric endpoints. Specific Aim #2: characterize the caudal sperm and testis mRNA and miRNA transcript content. Specific Aim #3: develop the caudal sperm and testis methylome.

双酚A（BPA）是一种内分泌干扰化学品，在发达国家中引起普遍暴露。 世界动物研究和最近的流行病学证据都表明，BPA的目标是男性 生殖tracl<，导致睾丸损伤和精子参数改变。 啮齿动物模型中基于GLP的标准方法在检测BPA诱导的 男性生殖道异常我们建议使用公认的形态测量 睾丸的评估，包括保留的精子细胞头的定量和TUNEL阳性的发生率 生殖细胞，以提高检测BPA暴露对睾丸影响的灵敏度。另外我们 将通过检测整体mRNA和miRNA， 水平和全基因组DNA甲基化。测量精子中的这些分子生物标志物有望 特别敏感和特异，因为精子是一个同质的细胞群体， 在生精上皮内的整个生命史中。GLP设计提供了多次给药， 阳性雌二醇对照，允许对BPA诱导效应的存在进行稳健测试。另外我们 将评估父系FO大鼠及其后代，解决跨代差异。目标 本项目的目的是测试以下工作假设：增加增强的形态和 GLP设计的分子终点将提供更敏感和特异的BPA诱导的生物标志物， 雄性生殖毒性。 GLP研究将通过形态学评估和效应的分子生物标志物来增强 通过以下具体目标： 具体目标#1：将使用先进的 组织学和形态学终点。 具体目标#2：表征尾部精子和睾丸mRNA和miRNA转录本含量。 具体目标#3：开发尾部精子和睾丸甲基化组。