GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health

GEMS：将种系突变率升高与男性不育和躯体健康联系起来的基因组方法

• 批准号: 10643716
• 负责人: Kenneth Ivan Aston
• 金额: $ 76.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643716
• 关键词: Age; Andrology; Automobile Driving; Autopsy; Blood; Cadaver; Cardiovascular Diseases; Cause of Death; Childhood Leukemia; Clinic; Colon; Colon Carcinoma; Complex; Consensus; DNA; DNA sequencing; Data; Data Set; Electronic Health Record; Environment; Epidemiology; Etiology; Family; Family member; Fertility; Follow-Up Studies; Generations; Genetic; Genomic Instability; Genomic approach; Genomics; Germ Cells; Germ-Line Mutation; Goals; Health; Hereditary Malignant Neoplasm; Heritability; Human; Incidence; Individual; Infertility; Life Style; Link; Longevity; Male Infertility; Malignant Childhood Neoplasm; Malignant neoplasm of prostate; Malignant neoplasm of testis; Malignant neoplasm of thyroid; Maps; Measures; Mosaicism; Mutation; Organ; Organ Donor; Paternal Age; Population; Population Database; Prostate; Reproduction; Research; Risk; Sampling; Somatic Cell; Somatic Mutation; Sperm Banks; Sperm Count Procedure; Subfertile Men; Testing; Testis; Tissue Banks; Tissue Donors; Tissues; Utah; Work; assisted reproduction; cancer risk; cohort; congenital anomaly; de novo mutation; deep sequencing; disorder risk; epidemiologic data; genetic pedigree; genome sequencing; high risk; high risk men; human tissue; leukemia/lymphoma; men; offspring; prostate cancer risk; reproductive; sperm cell; stem cells; subfertility

PROJECT SUMMARY / ABSTRACT Male infertility impacts up to 7% of all men and has been shown to be associated with poor somatic health and elevated individual and familial cancer risk. Significant epidemiological data links male infertility to poorer somatic health compared with fertile men, manifesting as increased individual risks for prostate cancer, testis cancer, colon cancer, cardiovascular disease and reduced life span. Recent work by our group has also demonstrated that family members of infertile men are at higher risk of testis cancer and both major congenital anomalies and pediatric cancer. Specifically, much of this work found different associations in men with severe oligozoospermia (reduced sperm counts) compared with those with azoospermia, suggesting that their etiologies are fundamentally different. In a follow up study that mined age and cause of death information from the Utah Population Database (UPDB), we found that individuals with the highest quartile of age-adjusted germline mutation rates live for five fewer years than those in the lowest quartile. This project aims to study a unique population to measure mutations in the testis, mature sperm, and somatic tissue to test the hypotheses that genomic instability underlies reduced fertility, and that genome instability in one’s germline is connected to increased somatic mutation and mosaicism. We will test this through two aims. 1.) Assessment of whether subfertile men have higher germline mutation rates than fertile men by examining complex pedigree data to identify familial associations between male infertility and cancer risk and determine mutation rates in the germline and somatic cells of 20 oligozoospermic men and 20 hyperzoospermic men. 2.) We will test whether higher germline mutation rates are predictive of elevated somatic mutation rates and lower sperm counts by using cadaveric organ donor tissue from testis, sperm, prostate, blood and colon to assess mutation rates. These two aims will provide foundational datasets for the field and will be able to answer whether higher de-novo mutation rates are the mechanistic link underlying both male infertility and poor somatic health.

项目摘要/摘要

项目成果

The impact of socioeconomic status on bulk semen parameters, fertility treatment, and fertility outcomes in a cohort of subfertile men.

社会经济地位对生育力低下男性群体的大量精液参数、生育治疗和生育结果的影响。

• DOI: 10.1016/j.fertnstert.2023.02.015
• 发表时间: 2023
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Horns,JoshuaJ;Fendereski,Kiarad;Ramsay,JoemyM;Halpern,Joshua;Iko,IjeomaN;Ferlic,Elizabeth;Emery,BenjaminR;Aston,Kenneth;Hotaling,James
• 通讯作者: Hotaling,James

Environmental exposure to industrial air pollution is associated with decreased male fertility.

环境暴露于工业空气污染与男性生育能力下降有关。

• DOI: 10.1016/j.fertnstert.2023.05.143
• 发表时间: 2023
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Ramsay,JoemyM;Fendereski,Kiarad;Horns,JoshuaJ;VanDerslice,JamesA;Hanson,HeidiA;Emery,BenjaminR;Halpern,JoshuaA;Aston,KennethI;Ferlic,Elisabeth;Hotaling,JamesM
• 通讯作者: Hotaling,JamesM