High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring

Abstract

ObjectivesChronic and high consumption of fat constitutes an environmental stress that leads to metabolic diseases. We hypothesized that high-fat diet (HFD) transgenerationally remodels the epigenome of spermatozoa and metabolism of the offspring.MethodsF0-male rats fed either HFD or chow diet for 12 weeks were mated with chow-fed dams to generate F1 and F2 offspring. Motile spermatozoa were isolated from F0 and F1 breeders to determine DNA methylation and small non-coding RNA (sncRNA) expression pattern by deep sequencing.ResultsNewborn offspring of HFD-fed fathers had reduced body weight and pancreatic beta-cell mass. Adult female, but not male, offspring of HFD-fed fathers were glucose intolerant and resistant to HFD-induced weight gain. This phenotype was perpetuated in the F2 progeny, indicating transgenerational epigenetic inheritance. The epigenome of spermatozoa from HFD-fed F0 and their F1 male offspring showed common DNA methylation and small non-coding RNA expression signatures. Altered expression of sperm miRNA let-7c was passed down to metabolic tissues of the offspring, inducing a transcriptomic shift of the let-7c predicted targets.ConclusionOur results provide insight into mechanisms by which HFD transgenerationally reprograms the epigenome of sperm cells, thereby affecting metabolic tissues of offspring throughout two generations.

Paternal epigenetic programming: evolving metabolic disease risk

“…Studies that have examined methylation in sperm of metabolically compromised founding sires (Martinez et al 2014, Radford et al 2014, Wei et al 2014, de Castro Barbosa et al 2016 have found similarly widespread, modest changes to DNA methylation patterns. Several studies have assessed methylation defects in both sperm of the founding sires and somatic tissue from the offspring.…”

“…HFD-induced obesity in R162 Review s s j hur and others Paternal metabolic programming 58 3 : R162 Review male mice can propagate obesogenic and diabetogenic phenotypes through F1 and into (with incomplete penetrance) F2 offspring (Fullston et al 2013). More robust multigenerational programming by paternal HFD has also recently been reported in rats, where two generations of offspring had reduced birthweight and impaired glucose tolerance; interestingly, the female F1 and F2 offspring of HFD sires were also resistant to diet-induced obesity (de Castro Barbosa et al 2016). Mice that program impaired glucose tolerance and insulin sensitivity in their offspring after low-dose streptozotocin treatment appear to program in turn the same prediabetic phenotype in a succeeding generation of males (Wei et al 2014).…”

“…Several studies have assessed methylation defects in both sperm of the founding sires and somatic tissue from the offspring. Some of these report no overlap (Carone et al 2010, de Castro Barbosa et al 2016, whereas others report commonalities of very modest changes (Martinez et al 2014, Wei et al 2014. But DNA methylation changes that are small in magnitude are necessarily mosaic.…”

“…Despite this uncertainty, multiple studies have implicated sncRNA in paternal programming effects, and these examples are not restricted to metabolism, suggesting a pervasive role for RNA in mediating paternal effects. Changes to sperm sncRNA composition have been reported in a range of induced traits (Wagner et al 2008 Gapp et al 2014, Rodgers et al 2015, including paternal metabolic compromise (Chen et al 2016, Cropley et al 2016, de Castro Barbosa et al 2016, Sharma et al 2016. Like studies of DNA methylation in paternal metabolic programming, studies of the well-characterized microRNAs have yielded results idiosyncratic to the model system.…”

Thermo Stability of DNA Methylation Marks in Human Sperm

“…Because of the dynamic nature of this mark in mammalian sperm, it is susceptible to alterations via cellular processes based on exposure to multiple modifiers including various toxins, pollutants, diet alterations, stress exposures and even age [4][5][6]. While some of these alterations are likely quite benign, it has been shown in recent studies that specific patterns of epigenetic alteration are associated with various abnormalities in sperm biology and have additionally been associated with subfertility [7][8][9].…”