Diet‐Induced Paternal Obesity Impairs Cognitive Function in Offspring by Mediating Epigenetic Modifications in Spermatozoa

Abstract

Objective This study aimed to determine the effects of diet‐induced paternal obesity on cognitive function in mice offspring. Methods Male mice (F0) were randomized to receive either a control diet (10 kcal% fat) or a high‐fat diet (HFD; 60 kcal% fat) for 10 weeks before being mated with normal females to generate F1 offspring. Male F1 offspring were mated with normal females to generate F2 offspring. Behavioral tests were used to assess cognitive functions in F1 and F2 offspring. Reduced representation bisulfite sequencing was used to the explore mechanisms of epigenetic inheritance. Results HFD‐induced paternal obesity resulted in cognitive impairments in F1 offspring, potentially due, at least in part, to increased methylation of the BDNF gene promoter, which was inherited from F0 spermatozoa. BDNF/tyrosine receptor kinase B signaling was associated with cognitive impairments in HFD‐fed F1 offspring. However, there were no significant changes in F2 offspring. Conclusions The findings provide evidence of intergenerational effects of paternal obesity on cognitive function in offspring occurring via epigenetic spermatozoan modifications.

An Evolutionary Perspective on Why Food Overconsumption Impairs Cognition

“…Consistent with the latter possibility, animal studies have shown that pups born to obese dams exhibit heightened and anxiety and depression-like behaviors [101]. Paternal obesity may also adversely impact cognitive and behavioral outcomes in offspring by epigenetic mechanisms [102,103]. Collectively, the emerging data suggest that overconsumption of high-energy foods by conceiving mothers and fathers increase the risk of poor or suboptimal cognitive outcomes of their offspring.…”

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

“…Epigenetic inheritance refers to heritable changes in phenotypes that are independent of changes to the DNA sequence. Environmental insults, such as change in diet (Carone et al 2010;Dunn and Bale 2011;Watkins et al 2018;Zhou et al 2018), exposure to drugs of abuse (Le et al 2017;Vassoler et al 2013;Yohn et al 2015), and stress (Bale 2015;Morgan and Bale 2011;Rodgers et al 2013b;Rodgers et al 2015) have been shown to cause epigenetic changes in male germ cells. Exposure to drugs of abuse changes several components of the epigenetic landscape, including acetylation of histones and DNA methylation in sperm of both rodents (Le et al 2017;Vassoler et al 2013) and humans (Chorbov et al 2011).…”

Parental Weight Status and Offspring Behavioral Problems and Psychiatric Symptoms

“…28 Paternal obesity may also relate to child behavioral problems or psychiatric symptoms as evidence from animal studies has revealed mechanisms for non-mendelian epigenetic inheritance. 29 Previous studies investigated the associations of paternal obesity with child behavioral problems and psychiatric symptoms; two did not find an association between paternal obesity and child behavioral problems 12,18 , one observed a positive, but imprecise, association with ADHD symptoms, 26 and, in the largest study, a positive association between paternal obesity and offspring behavioral problems was observed. 15 An association with maternal but not paternal obesity would support the hypothesis that alterations in the intrauterine environment, rather than preconception or postnatal factors shared between parents (e.g., diet)are implicated in the development of offspring behavioral problems and psychiatric symptoms.…”