Paternal exposure to dioxins and offspring sex ratio distortion

 描述(申请人提供)：父亲接触二恶英和后代性别比扭曲项目摘要/摘要人们普遍认为，某些男性生殖障碍(如精液质量受损、睾丸癌、隐睾症和尿道下裂)的发生率正在增加，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。在这项提案中，这些特定效应之一，即暴露于2，3，7，8-四氯二苯并-对二恶英(TCDD或二恶英)的人和动物雄性后代导致性别比扭曲的复杂生物学机制将被阐明。广泛的、长期的目标是确定导致接触TCDD等化合物的雄性哺乳动物后代的性别比传递扭曲的机制。需要检验的假设是：某些环境毒物通过改变连接的、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，降低了Y精子的相对有效性。具体目标1是为研究父亲接触二恶英引起的性别比传递扭曲提供实验条件。要测试的假设是：作为TCDD暴露的结果，表达高反应性AHR的近交系小鼠将比具有对TCDD不太敏感的AHR的品系表现出更大的性别比扭曲。我们将优化观察性别比扭曲的条件，并期望发现AHR是TCDD诱导的性别比扭曲所必需的。 具体目标2是阐明暴露于TCDD或未暴露于TCDD的X和Y精子细胞之间的特定mRNA水平的差异。需要检验的假设是：TCDD通过AHR作用，改变影响X和Y精子相对功能的一个或多个基因的mRNA水平。我们预计，影响X或Y精子受精能力的特定基因是有差异表达的。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/丰富的一种手段)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。短期内，研究环境毒物对人类和动物生殖的影响将揭示接触二恶英的人类性别比扭曲的机制。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，以提高农业上重要物种的女婴比例。

 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.