Stress-Induced Father-Mediated 45s Rrna Genetic And Epigenetic Reprogramming

Environmental and dietary factors modify genomes and phenotypes. The extents of these modifications are not clear. DNA methylation and genotypes of the multi-copy 45S rRNA gene were quantified in 4 tissues at 3 developmental stages (sperm of 128 treated males, 98 litters of 876 day-8 embryos, and lung, liver, and a subset of sperm from 93 litters of 758 6-week adult offspring) in 3 treatment groups. Mixed models for adjusting confounding factors were used for all statistical analyses. Single injections of 1 mmol/kg chromium(III), [Cr(III)], an environmental agent and a dietary supplement, or acid saline (AS) vehicle were given to male mice only, which were then euthanized or bred 2 weeks later. A trend toward hypomethylation in the rRNA spacer promoter region but no frequency differences in 5 sequence variants of the rRNA, defined by 4 single nucleotide polymorphisms, were observed in sperm 2 weeks after Cr(III) treatment as compared to AS and untreated (UT) groups. This epigenetic trend disappeared at the day-8 embryo stage for both genders after paternal treatments with Cr(III) and/or AS. In offspring at 6 weeks of age, significant hypermethylation of the rRNA spacer-promoter was detected in the lung of the male offspring from Cr(III)-treated fathers, reversing the hypomethylation trend seen in the sperm 2 weeks after Cr(III) treatment. There was also a change in genotype: a significant reduction of the rRNA CGC variant in Cr(III) and/or AS groups in lung and liver in males, and in lung in females. Further examinations of the regressions of individual sequence variants on DNA methylation and on other variants revealed significant modifications to those correlates by Cr(III) and/or AS but to different degrees depending on the developmental stages, thus supporting the hypothesis of paternal exposure-induced epigenetic and genetic reprogramming. These genomic reprogrammings were accompanied by phenotypic changes related to paternal Cr(III) or AS treatment, including increased body and liver weights and alterations in serum glucose and leptin. Male mice treated with either Cr(III) or AS demonstrated a typical chemical stress response, as indicated by acute reduction in serum insulin and leptin, followed later by increases in these hormones. Taken together, this multi-faceted cross-generational study uncovers modifiable epigenetic and genetic reprogramming during development and differentiation. Paternal stress apparently had multiple effects on genomes and phenotypes, in their offspring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 184.