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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.