Our projects: Intergenerational programming of reno-vascular function

We have long been interested in the impact of maternal undernutrition upon cardiovascular function across several generations. Just a few years after our first demonstration that protein restriction in rat pregnancy resulted in higher blood pressure in the exposed offspring, we showed that the effect could also be transmitted to a second generation (published as an abstract only Dunn et al. Proc Nutr Soc 1996). Funding from the British Heart Foundation (PI Simon Langley-Evans) enabled us to investigate this in more detail and across three generations.

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Working with then PhD student, Matt Harrison, we carried out a study in which protein restricted rat dams (F0) were used to generate male and female F1 offspring. These were then used to generate F2 without further dietary insult and the F2 produced an F3 generation. In the F1 generation exposure to protein restriction was associated with higher blood pressure and a reduced nephron number, which is out well-characterised programmed phenotype. We generated 4 groups of F2 offspring by crossing male controls with female controls, low protein males with control females, control males with low protein females and low protein male and females. The phenotype observed in the F1 generation was also present in all F2 groups, showing that not only did programming have an intergenerational effect, that effect could be passed down both the male and female lineage. By F3 the effect was no longer observable.

Initial analysis of the tissues collected from this experiment suggested that there were some genes associated with hypertension that may be differentially expressed across F1, F2 and F3. We are now working in collaboration with Dr Elia Stupka and colleagues at the San Raffaele Institute in Milan to investigate this further. We have considered maternal diet related effects on the epigenome in F1, F2 and F3 generations and have observed clear evidence of differential DNA methylation related to the original dietary insult, across all three generations. We are now using RNASeq to evaluate the relationship between DMRs in known gene promoter regions and gene expression.

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