Abstract
BackgroundEarly life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring. These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. We have previously shown that prenatal overexposure to the synthetic glucocorticoid dexamethasone (Dex) in rats reduces birth weight in the first generation (F1), a phenotype which is transmitted to a second generation (F2), particularly through the male line. We hypothesize that Dex exposure affects developing germ cells, resulting in transmissible alterations in DNA methylation, histone marks and/or small RNA in the male germline.ResultsWe profile epigenetic marks in sperm from F1 Sprague Dawley rats expressing a germ cell-specific GFP transgene following Dex or vehicle treatment of the mothers, using methylated DNA immunoprecipitation sequencing, small RNA sequencing and chromatin immunoprecipitation sequencing for H3K4me3, H3K4me1, H3K27me3 and H3K9me3. Although effects on birth weight are transmitted to the F2 generation through the male line, no differences in DNA methylation, histone modifications or small RNA were detected between germ cells and sperm from Dex-exposed animals and controls.ConclusionsAlthough the phenotype is transmitted to a second generation, we are unable to detect specific changes in DNA methylation, common histone modifications or small RNA profiles in sperm. Dex exposure is associated with more variable 5mC levels, particularly at non-promoter loci. Although this could be one mechanism contributing to the observed phenotype, other germline epigenetic modifications or non-epigenetic mechanisms may be responsible for the transmission of programmed effects across generations in this model.
Highlights
Life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring
We have previously shown that this phenotype can be transmitted to a second (F2) but not a third generation: F2 offspring of male or female rats exposed to the synthetic glucocorticoid dexamethasone (Dex) have a lower birth weight and exhibit hyperglycaemia in adulthood and the transmitted phenotype is stronger through the male line [26, 28]
Consistent with our previous studies [26, 28], pup and placenta weight was reduced at E19.5 in Dexexposed pups (Fig. 1b) and birth weight was reduced in the F1 offspring of Dex-treated dams (Fig. 1c) and in the F2 offspring of F1 Dex males mated with F1 vehicle-treated (Veh) females (Fig. 1d)
Summary
Life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. Whilst transmission through the maternal line may be attributed to reexposure via altered maternal physiology, or to changes in maternal behaviour [8, 9], paternal transmission in such animal models implicates effects transmissible through the germline, since in general in these models the male contributes little else to the offspring and its environment Such data have led to the suggestion that induced epigenetic marks may be transmissible through the gametes [6, 10]. Most histones are replaced by protamines in sperm, some histones are retained at key loci and evidence suggests that alterations in sperm histones may underpin the transgenerational transmission of phenotypes [21,22,23]
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