BPA: Cellular and epigenetic effects on the urethra

BPA：对尿道的细胞和表观遗传影响

基本信息

批准号：
8686851
负责人：
FREDERICK S VOM SAAL
金额：
$ 18.66万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686851
关键词：
2 year old Actins Acute Renal Failure with Renal Papillary Necrosis Adult Affect Age Aging Animal Model Animals Apoptosis Area Basal Cell Bioinformatics Bladder Breeding Candidate Disease Gene Cessation of life Chemicals Clinical Collagen Computer Assisted Computers Coupled Coupling Cytokeratin-8 Staining Method DNA DNA Methylation Data Decision Making Development Disease Dose Dysplasia Elastin Environmental Pollution Epigenetic Process Epithelial Epithelial Cells Epithelium Estradiol Estrogens Etiology Exhibits Exposure to Female Fetus Frequencies Gene Expression Genital system Genomic DNA Gland Goals Growth Histopathology Hyperplasia Immunohistochemistry In Situ Nick-End Labeling Instruction Kinetics Life Longevity MSMB gene Maps Messenger RNA Methods Molecular Profiling Morphology Mus Neonatal Outcome Perinatal Exposure Positioning Attribute Pregnancy Process Prostate Prostatic Prostatic Diseases Protocols documentation Rattus Research Research Personnel Role Serum Staining method Stains Stromal Cells Structure Symptoms Tissues Urethra Urethral Obstruction Urinary tract Urination Urine Urogenital Sinus Vimentin Woman base bisphenol A caspase-3 cell type computerized tools constriction fetal genome wide methylation gland development innovation laser capture microdissection mRNA Expression male malformation men next generation sequencing postnatal pregnant prenatal prenatal exposure pressure probasin programs protein expression reconstruction research study response urinary bladder neck

项目摘要

Obstructive voiding disorder (CVD) is a common disease during aging in men, and while less common, it aisc occurs in women. The proposed experiments concern the role of prenatal and postnatal (lifespan) exposure to bisphenol A (BPA) on the development of OVD in both male and female SD rats reared and treated with different doses of BPA under a GLP protocol at the NCTR. Preliminary studies with both male and female rats and mice show that changes in periurethral gland development and malformations ofthe urethra are caused by estrogenic chemicals, including BPA, but specific effects are different at low and high doses. Preliminary studies also show that prenatal exposure to BPA results in OVD in male mice exposed to exogenous estrogen during adulthood. Our hypothesis is that fetal exposure to low doses of BPA will predispose both male and female SD rats to development of OVD during aging as a result of continued exposure to the same dose of BPA during postnatal life. In specific aim 1 we will examine the effects of BPA on male and female fetal (gestation day 21) periurethral gland structure (using computer-assisted reconstruction of serial sections) and function of epithelium and stroma, using laser capture microdissection (LCM) coupled with next generation sequencing (NGS) for examination of gene expression and epigenetic changes in DNA, as well as immunohistochemistry to identify specific cell types, proliferation and apoptosis. In Specific Aim 2 the urethra will be collected from adult male and female rats that develop OVD or at specific ages in non-diseased controls. We will examine periurethral gland and stroma structure and function using the same outcomes described for fetuses (histopathology, immunohistochemistry, LCM to capture epithelial and stromal cells for analysis of mRNA and genomic DNA using NGS to determine transcriptomal profiles and to determine genome-wide methylation profiles of genomic DNA. The combination of detailed morphological and functional analyses of fetal and adult urethral tissues exposed to different doses of BPA is highly innovative.

阻塞性排尿障碍 (CVD) 是男性衰老过程中的一种常见疾病，虽然不太常见，但它也是一种常见疾病。发生于女性。拟议的实验涉及产前和产后（寿命）暴露的作用双酚 A (BPA) 对饲养和治疗的雄性和雌性 SD 大鼠 OVD 发展的影响根据 NCTR 的 GLP 协议，使用不同剂量的 BPA。对男性和女性的初步研究大鼠和小鼠显示尿道周围腺体发育的变化和尿道畸形由雌激素化学物质（包括 BPA）引起，但低剂量和高剂量的具体效果不同。初步研究还表明，产前接触 BPA 会导致雄性小鼠出现 OVD 成年期外源性雌激素。我们的假设是，胎儿接触低剂量的 BPA 会雄性和雌性 SD 大鼠在衰老过程中由于持续的产后生活中接触相同剂量的 BPA。在具体目标 1 中，我们将检查 BPA 的影响对男性和女性胎儿（妊娠第 21 天）尿道周围腺体结构（使用计算机辅助使用激光捕获显微切割重建连续切片）以及上皮和基质的功能 (LCM) 与下一代测序 (NGS) 相结合，用于检查基因表达和表观遗传 DNA 的变化以及免疫组织化学来识别特定的细胞类型、增殖和凋亡。在具体目标 2 中，将从发生 OVD 或特定情况下的成年雄性和雌性大鼠中采集尿道。未患病对照的年龄。我们将使用以下方法检查尿道周围腺和基质的结构和功能与胎儿描述的结果相同（组织病理学、免疫组织化学、LCM 捕获上皮细胞）和基质细胞，使用 NGS 分析 mRNA 和基因组 DNA，以确定转录组谱并确定基因组 DNA 的全基因组甲基化谱。详细的组合对暴露于不同剂量 BPA 的胎儿和成人尿道组织进行形态学和功能分析高度创新。