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（由申请人提供）：父亲暴露于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，隐睾症和尿道下裂）的发病率正在增加，这些变化可能在很大程度上是由环境中的有毒物质引起的。在这项提案中，这些具体的影响之一，复杂的生物学机制的性别比例扭曲所造成的人类和动物的男性接触到2，3，7，8-四氯二苯并-p-二恶英（TCDD或二恶英）的后代，将被阐明。广泛的，长期的目标是确定的机制，导致传播扭曲的性别比例的雄性哺乳动物，已暴露于化合物，如四氯二苯并对二恶英。待检验的假设是：某些环境毒物通过改变联合的、同步发育的单倍体精子细胞跨细胞间桥共享RNA和/或蛋白质的能力，或通过差异影响来自携带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，降低Y精子的相对有效性。具体目标1是改善研究父源二恶英暴露导致的性别比例传递失真的实验条件。要检验的假设是：作为TCDD暴露的结果，表达高反应性AHRs的近交系小鼠将表现出比具有对TCDD反应较低的AHRs的品系更大的性比失真。我们将优化观察性别比例畸变的条件，并期望发现TCDD诱导的性别比例畸变需要AHR。 具体目标2是阐明X和Y精子细胞之间的特定mRNA水平的差异，有或没有暴露于TCDD。待检验的假设是：TCDD通过AHR起作用，改变影响X和Y精子相对功能的基因的mRNA水平。我们预期特定基因的差异表达会影响X或Y精子使卵子受精的能力。在后代中产生适当的性别比例对生物医学（人类健康后果），生态学（物种保护）以及潜在的农业（作为后代性别选择/富集的手段）都很重要。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。从短期来看，研究环境毒物对人类和动物生殖的影响将揭示二恶英暴露人群性别比例扭曲的机制。从长远来看，该项目资助的实验可能导致开发有益的药物化合物，以增加农业重要物种的雌性生育率。