A mouse model of paternal obesity alters gene expression and methylation status of the testes and germ cells, subsequently impairing the metabolic health of two generations. — ASN Events
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A mouse model of paternal obesity alters gene expression and methylation status of the testes and germ cells, subsequently impairing the metabolic health of two generations. (#342)

Tod Fullston 1 , Julie A Owens 1 , Nicole O Palmer 1 , Megan Mitchell 1 , Miles J DeBlasio 1 , Cristin G Print 2 , Hassan W Bakos 1 , Michelle Lane 1
  1. Discipline of Obstetrics & Gynaecology, School of Paediatrics and Reproductive Health, Robinson Institute, The University of Adelaide, Adelaide, SA, Australia
  2. Molecular Medicine & Pathology and New Zealand Bioinformatics Institute, University of Auckland, Auckland, New Zealand

Obesity is becoming increasingly prevalent, if not epidemic.  It has been previously shown that a rodent chronic paternal exposure to a high fat diet (HFD) induces diabetes and obesity, resulting in glucose intolerance in female F1 offspring.

We demonstrate that a mouse model of HFD induced paternal obesity induced, in the absence of diabetes, initiates intergenerational transmission of obesity and insulin resistance to offspring through two generations.  This is the first demonstration of this specific constellation of phenotypes being transmitted by paternal to both F1 males/females and subsequently to the F2 generation.  Furthermore, we show that insulin resistance is transmitted through the F1 paternal line to females and via the F1 maternal line to males.

Founder male obesity also associated with a reduction of testis and germ cell global methylation.  Microarray interrogation demonstrated that paternal obesity altered gene expression in the testes.  Pathway analysis implicated that perturbations to the following signalling cascades were caused by the obese state: androgen; estrogen; relaxin; EIF2; NF-χβ; TGF-β; and sertoli cell junction signalling.  Other candidate processes implicated by altered molecular expression include spermatogenesis, reactive oxygen species production, lipid metabolism, carbohydrate metabolism, anti-oxidant scavenging and inflammatory responses.  We speculate that these perturbed processes might in part act to initiate the observed programming of offspring by alterations to the testicular environment, which in turn alters the molecular makeup of the obese male’s gametes.

This is evidence that the nutritional status of the father alters methylation and gene expression in the testis and germ cells that potentially form part of a signal that can subsequently program offspring health.  This is the first observation of paternal transmission of obesity and metabolic health impairment to future generations via both sexes of the first generation.  This indicates that further investigations into the transgenerational amplification of obesity and type 2 diabetes in humans are clearly warranted.