Impact of Metabolic Health on Sperm Epigenetic Marks in Humans

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.

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