Paternal exposure to dioxins and offspring sex ratio distortion

父亲接触二恶英与后代性别比扭曲

• 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
• 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

 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（由适用提供）：父亲暴露于二恶英和后代性别比例失真项目摘要/摘要中，人们广泛认识到，某些男性生殖疾病的发生率（例如，精液质量，测试癌症，隐化型和造o刺菌和缺失）的发生率正在增加，并且这些变化可能在整个毒性中可能导致这些变化。在此提案中，这些特定效应之一是，将阐明暴露于2,3,7,8-四氯迪本佐-P-二恶英（TCDD或二恶英）的人和动物雄性后代引起的性别比扭曲的复杂生物学机制。广泛的长期目标是定义导致雄性哺乳动物生成的后代的传播扭曲的机制，而男性哺乳动物已暴露于TCDD等化合物。要检验的假设是：某些环境有毒物质通过改变结合，同步发展单倍体的精子在跨间桥上共享RNA和/或蛋白质的能力来降低Y精子的相对有效性精子）。具体目的1是增强研究性别比率传播失真导致父亲二恶英暴露导致的实验条件。要测试的假设是：由于TCDD暴露，表达高度响应AHR的小鼠的近交菌株比具有对TCDD响应较低的AHR的菌株表现出更大的性别比变形。我们将优化观察性别比扭曲的条件，并希望发现TCDD诱导的性别比失真所必需的AHR。 具体目的2是阐明X和Y精子之间的特定mRNA水平的差异或尚未暴露于TCDD的差异。要检验的假设是：TCDD，通过AHR作用，改变了影响X和Y精子相对功能的基因或基因的mRNA水平。我们预计特定基因的表达不同，会影响X或Y精子施肥卵的能力。在后代中产生适当的性别比对于生物医学（人类健康后果），生态学（物种保存）以及可能同意（作为后代性别选择/富集的一种手段）至关重要。在这些研究中，使用小鼠作为人类的替代物，我们将获得重要的知识，这些知识将适用于辅助生殖，生殖细胞生物学和成人疾病的发育起源。在短期内，研究对环境有毒物质对人类和动物繁殖的影响的研究将发现二恶英暴露的人的性别比失真机制。从长远来看，该项目资助的实验可能导致有益的药物化合物的发展，以增加农业重要物种的女性出生比率。