Paternal Methyl Donor Supplementation in Rats Improves Fertility, Physiological Outcomes, Gut Microbial Signatures and Epigenetic Markers Altered by High Fat/High Sucrose Diet

Faye Chleilat,Alana Schick,Julie M Deleemans,Raylene A Reimer

doi:10.3390/ijms22020689

Faye Chleilat, Alana Schick + Show 2 more

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https://doi.org/10.3390/ijms22020689

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Abstract

Increased consumption of high fat/sucrose (HF/S) diets has contributed to rising rates of obesity and its co-morbidities globally, while also negatively impacting male reproductive health. Our objective was to examine whether adding a methyl donor cocktail to paternal HF/S diet (HF/S+M) improves health status in fathers and offspring. From 3–12 weeks of age, male Sprague Dawley rats consumed a HF/S or HF/S+M diet. Offspring were followed until 16 weeks of age. Body composition, metabolic markers, gut microbiota, DNA methyltransferase (DNMT) and microRNA expression were measured in fathers and offspring. Compared to HF/S, paternal HF/S+M diet reduced fat mass in offspring (p < 0.005). HF/S+M fathers consumed 16% fewer kcal/day, which persisted in HF/S+M female offspring and was explained in part by changes in serum glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels. Compared to HF/S, HF/S+M fathers had a 33% improvement in days until conception and 300% fewer stillbirths. In fathers, adipose tissue DNMT3a and hepatic miR-34a expression were reduced with HF/S+M. Adult male offspring showed upregulated miR-24, -33, -122a and -143 expression while females exhibited downregulated miR-33 expression. Fathers and offspring presented differences in gut microbial signatures. Supplementing a paternal HF/S diet with methyl-donors improved fertility, physiological outcomes, epigenetic and gut microbial signatures intergenerationally.

Highlights

Growing evidence suggests that the decline in male reproductive fitness globally, is in part due to the growing obesity epidemic [1]
No difference in body weight was observed between diets in male (Figure 1B) or female (Figure 1C) offspring; we observed important differences in body composition, wherein male and female high fat/sucrose (HF/S)+M offspring had significantly lower fat mass compared to HF/S offspring, even though both groups consumed the same, nutritionally complete, American Institute of Nutrition (AIN)-93 diet for 13 weeks (Table 1)
We present evidence that supplementing a paternal HF/S diet with a methyl-donor cocktail of betaine, choline, folic acid and vitamin B12 before conception reduced energy intake, fasting serum insulin and insulin resistance alongside alterations in gut microbial signatures, epigenetic markers modulating metabolism, and reproductive outcomes in fathers

Summary

Introduction

Growing evidence suggests that the decline in male reproductive fitness globally, is in part due to the growing obesity epidemic [1]. Human [2,3] and animal studies [4] have shown that high fat diets, which often reflect poor nutritional status and contribute to increased body mass index (BMI), have been associated with compromised sperm quality, embryo development and fetal growth. High fat diet-induced hyperglycemia, hyperinsulinemia and hypercholesterolemia are associated with alterations in testicular morphology [7,8]. The relationship between male reproductive health and obesity is predictable based on the fact that cholesterol is the chief metabolic precursor involved in testosterone synthesis [9] and the principal spermatogenesis regulator [10], both of which are modulated in part by epigenetics. Among the most widely studied epigenetic mechanisms are DNA methylation and non-coding RNA expression [12]

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