Paternal exposure to dioxins and offspring sex ratio distortion

父亲接触二恶英与后代性别比扭曲

基本信息

批准号：
8969872
负责人：
George L. Gerton
金额：
$ 24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969872
关键词：
Adolescent Adult Adverse effects Affect Agriculture Alleles Animals Aryl Hydrocarbon Receptor Barker Hypothesis Biological Biological Preservation Birth Cellular biology Complex Cryptorchidism Development Dioxins Disease Ecology Effectiveness Environment Exhibits Exposure to Female Fertilization Funding Future Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Germ Cells Goals Haploidy Health Human Hypospadias Inbred Strains Mice Knowledge Lead Learning Male Infertility Malignant neoplasm of testis Mammals Messenger RNA Modeling Mus Paternal Exposure Pharmacologic Substance Poison Predisposition Proline Proteins RNA Relative (related person)Reproduction Seminal fluid Sex Preselection Sex Ratio Spermatids Testing Tetrachlorodibenzodioxin Toxic Environmental Substances X Chromosome X-Bearing Sperms Y Chromosome Y-Bearing Sperms abstracting assisted reproduction base differential expression insight male offspring public health relevance reproductive research study sex sperm cell transcription factor transmission process zygote

项目摘要

DESCRIPTION (provided by applicant): Paternal exposure to dioxins and offspring sex ratio distortion Project Summary/Abstract It is widely recognized that the rates of certain male reproductive disorders (such as impaired semen quality, testicular cancer, cryptorchidism, and hypospadias) are increasing and that these changes may be caused in large part by toxic substances in the environment. In this proposal, one of these specific effects, the complex biological mechanism of sex ratio distortion caused in the offspring of human and animal males exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), will be elucidated. The broad, long-term goal is to define the mechanism that causes transmission distortion in the sex ratios of offspring sired by male mammals that have been exposed to compounds such as TCDD. The hypothesis to be tested is: Certain environmental toxicants decrease the relative effectiveness of Y sperm by altering the ability of conjoined, synchronously developing haploid spermatids to share RNA and/or proteins across intercellular bridges or by differentially impacting gene expression from the X chromosome- bearing spermatids (X spermatids) or Y chromosome-bearing spermatids (Y spermatids). Specific Aim 1 is to enhance the experimental conditions for the study of sex ratio transmission distortion resulting from paternal dioxin exposure. The hypothesis to be tested is: As a consequence of TCDD exposure, inbred strains of mice that express highly responsive AHRs will exhibit greater sex ratio distortion than strains that have AHRs that are less responsive to TCDD. We will optimize the conditions for observing the sex ratio distortion and expect to find that AHR is required for the TCDD-induced sex ratio distortion. Specific Aim 2 is to elucidate the differences in specific mRNA levels between X and Y spermatids that have or have not been exposed to TCDD. The hypothesis to be tested is: TCDD, acting through the AHR, alters mRNA levels of a gene or genes affecting the relative functionality the X and Y sperm. We anticipate that specific genes are differentially expressed that influence the ability of X or Y sperm to fertilize an egg. Producing the proper sex ratio in offspring is important to biomedicine (human health consequences), ecology (preservation of species), and, potentially, agriculture (as a means for offspring sex selection/enrichment). Using the mouse as a surrogate for humans in these studies, we will gain important knowledge that will be applicable to assisted reproduction, germ cell biology, and the developmental origins of adult disease. In the short term, the study of the effects on environmental toxicants on human and animal reproduction will uncover the mechanism of sex ratio distortion in dioxin- exposed humans. In the long run, the experiments funded by this project could lead to the development of beneficial pharmaceutical compounds to increase the ratio of female births of agriculturally important species.

描述（由申请人提供）：父亲接触二恶英和后代性别比例扭曲项目摘要/摘要人们普遍认为，某些男性生殖疾病（如精液质量受损、睾丸癌、隐睾和尿道下裂）的发病率正在增加，并且认为这些变化在很大程度上可能是由环境中的有毒物质引起的。在这项提议中，这些具体影响之一是在人类和动物雄性暴露于其后代时造成性别比例扭曲的复杂生物机制。 2,3,7,8-四氯二苯并-对二恶英（TCDD或二恶英）将被阐明，广泛的长期目标是确定导致雄性哺乳动物生育的后代性别比例传递扭曲的机制。已暴露于 TCDD 等化合物。待检验的假设是：某些环境毒物通过改变连体、同步发育的单倍体精子细胞共享 RNA 的能力来降低 Y 精子的相对有效性。和/或跨细胞间桥的蛋白质，或通过差异性地影响携带 X 染色体的精子细胞（X 精子细胞）或携带 Y 染色体的精子细胞（Y 精子细胞）的基因表达。具体目标 1 是增强性别比研究的实验条件。父系二恶英高度暴露导致的传输失真待检验的假设是：由于 TCDD 暴露，表达响应性 AHR 的小鼠近交品系将表现出比具有 AHR 的小鼠品系更大的性别比例失真。我们将优化观察性别比扭曲的条件，并期望发现 AHR 是 TCDD 引起的性别比扭曲所必需的。具体目标 2 是阐明已接触或未接触 TCDD 的 X 和 Y 精子细胞之间特定 mRNA 水平的差异。要测试的假设是：TCDD 通过 AHR 起作用，改变影响基因的 mRNA 水平。 X 和 Y 精子的相对功能我们预计，特定基因的表达会影响 X 或 Y 精子使卵子受精的能力，这对生物医学（人类健康）很重要。在这些研究中使用小鼠作为人类的替代品，我们将获得适用于辅助的重要知识。生殖、生殖细胞生物学和成人疾病的发育起源在短期内，研究环境毒物对人类和动物生殖的影响将揭示长期接触二恶英的人类性别比例扭曲的机制。 , 本次资助的实验该项目可能会导致药用有益化合物的开发，以提高农业重要物种的雌性出生率。