Impact of Metabolic Health on Sperm Epigenetic Marks in Humans
キーワード
概要
説明
Parental history of type 2 diabetes (T2D) confers substantial individual risk for development of obesity and diabetes. Obesity risk can be transmitted across generations, from parents or grandparents to children. Genomic variation explains only a portion of this risk. Epigenetic modulation through DNA methylation, histone modification, or by noncoding RNAs, provide mechanisms to regulate gene activity independent of DNA sequence by determining which genes are turned on or off in response to environment or disease. Epigenetic changes can be stable over the lifespan providing a mechanism through which environmental exposures may impart long-term effects on gene expression and phenotypic outcome.
The maternal intrauterine environment is now well recognized to modify obesity and T2D disease risk of offspring. Fetuses carried by women who are obese, diabetic or suffer from suboptimal nutrition are at increased risk of insulin resistance, obesity, T2D, and cardiovascular disease risk as adults. Studies in rodents also show that the health, metabolism, and prior environmental exposures of the male can also influence health of his offspring. Existing data provide powerful support for the hypothesis that current metabolic health of males can alter epigenetic marks in sperm and suggest a novel modifiable mechanism of transmission. However, much less is known about how human sperm epigenetic patterns change with nutritional and metabolic health, and whether these may ultimately impart differences in health of future generations.
日付
| 最終確認済み: | 01/31/2019 |
| 最初に提出された: | 10/10/2018 |
| 提出された推定登録数: | 02/27/2019 |
| 最初の投稿: | 03/03/2019 |
| 最終更新が送信されました: | 02/27/2019 |
| 最終更新日: | 03/03/2019 |
| 実際の研究開始日: | 04/30/2018 |
| 一次完了予定日: | 04/30/2019 |
| 研究完了予定日: | 04/30/2019 |
状態または病気
介入/治療
Other: Lifestyle Intervention
Other: No Intervention
段階
アームグループ
| 腕 | 介入/治療 |
|---|---|
| Experimental: Lifestyle Intervention 20 overweight men with T1D or T2D will undergo an intensive 3 month lifestyle intervention program aimed at improving metabolic health, glycemic control, and body weight. | Other: Lifestyle Intervention Participants will undergo a 12-week multidisciplinary program for weight control and intensive diabetes management. The program includes adjustments to diabetes medications to enhance weight reduction and improve glycemia, dietary modification, and activity instructions. |
| Active Comparator: No-Intervention Controls 10 overweight men with T1D or T2D will be assessed at baseline and at 3 months. They will not participate in a lifestyle intervention. | |
| Active Comparator: Healthy Controls 10 healthy men will be assessed at baseline and at 3 months. They will not participate in a lifestyle intervention. |
適格基準
| 研究の対象となる年齢 | 18 Years に 18 Years |
| 研究に適格な性別 | Male |
| 健康なボランティアを受け入れる | はい |
| 基準 | Inclusion Criteria: - Male, age 18-65 years - Willing and able to provide informed consent and follow all study procedures, including providing sperm specimens 3 months apart. - Type 1 or type 2 diabetes diagnosis confirmed by an endocrinologist (for participants in the diabetes groups) - HbA1c > 7% (for participants in the diabetes groups) - Overweight (BMI > 25 kg/m2) (for all groups, to ensure groups are similar) Exclusion Criteria: - Chronic kidney disease stage 4 or 5 (including end-stage renal disease); - Hepatic disease, including serum ALT or AST greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0; - Severe diabetic retinopathy; - Congestive heart failure, NYHA class II, III or IV; - History of myocardial infarction, unstable angina or revascularization within the past 6 months; - Active genitourinary infection; - Testicular volume <12 mL (assessed using Prader orchidometer); - Hypogonadism, defined as total testosterone <250 ng/dl; - Hyperprolactinemia, defined as prolactin >18 ng/ml; - Hyperestrogenism, defined as estradiol >42 pg/ml; - Cryptorchidism; - Cigarette smoking; - Active alcohol abuse or substance abuse; - Cancer (except localized non-melanoma skin cancers) or use of chemotherapy agents within 5 years; - Use of nitrates or guanylate cyclase stimulators; - Use of steroid hormones (including testosterone), other than inhalers for reactive airway disease |
結果
主な結果の測定
1. Spermatozoa concentration [1 year]
二次的な結果の測定
1. Sperm DNA methylation, reported as genomic location of regions with methylation altered in response to intervention [1 year]
2. RNA Sequencing [1 year]
