BPA: Cellular and epigenetic effects on the urethra

BPA：对尿道的细胞和表观遗传影响

• 批准号: 8334563
• 负责人: FREDERICK S VOM SAAL
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 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/8334563
• 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; Genomics; Gland; Goals; Growth; Histopathology; Hyperplasia; Immunohistochemistry; In Situ Nick-End Labeling; Instruction; Kinetics; Life; Longevity; MSMB gene; Maps; Messenger RNA; Methods; Methylation; 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; gland development; innovation; laser capture microdissection; mRNA Expression; male; malformation; men; next generation; postnatal; pregnant; prenatal; prenatal exposure; pressure; probasin; programs; protein expression; reconstruction; research study; response; urinary bladder neck

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，但它是一种常见疾病