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Centre for Trophoblast Research

 

Supervised by: Amanda Sferruzzi-Perri (ans48@cam.ac.uk) & Gavin Kelsey (gavin.kelsey@babraham.ac.uk)

Project Title

Defining the contribution of parental obesity to feto-placental dynamics and offspring health

Project description

The prevalence of obesity is increasing at an alarming rate. In the UK alone, the majority of adults are overweight or obese, with >60% of men and women falling into this category and >25% being classified as obese. This is highly concerning as in addition to the widely known comorbidities associated with being overweight or obese, maternal or paternal overweight/obesity is linked to reproductive defects, including poor gamete quality and subsequent compromised fertility, pregnancy outcome and offspring health. Despite this, we lack information on the mechanisms linking parental obesity with poor pregnancy outcomes and subsequent offspring disease risk. Furthermore, the specific role of each parent and the combination of both parents being overweight/obese on pregnancy and offspring health has been largely unexplored. This study will endeavour to address these knowledge gaps by feeding female and male mice a control diet or a high fat diet to induce obesity prior to mating. Different combinations of matings between lean and obese mice with be set up and changes in fetal growth and placental formation and function during gestation will be examined. To identify the extent to which metabolic dysfunction is caused by maternal and/or paternal obesity, offspring metabolic health may then be determined. Finally, parental oocytes and sperm will be analysed to explore the role of changes in gamete quality and epigenetic status (mRNA, non-coding RNAs, DNA methylation) in the effect of parental obesity on prenatal development and offspring health. Data from parental gametes may be overlaid with transcriptome analyses of the fetus and placenta, to define the parental origin of identified RNAs and to establish the transmission stability from parents to the conceptus. The project will involve training in a variety of in vivo (e.g. placental nutrient transport assays, glucose/insulin tolerance tests, TdNMR scanning) and in vitro (e.g. RNAseq, cytochemistry, stereology, western blotting) techniques. The candidate will be expected to spend time in both of the CTR group leader’s labs, which will maximise skills training and knowledge advancement

References

  1. Musial B, Vaughan OR, Fernandez-Twinn DS, et al. A Western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice. The Journal of physiology. 2017;595(14):4875-4892.
  2. Fowden AL, Camm EJ, Sferruzzi-Perri AN. Effects of maternal obesity on placental phenotype Current Vascular Pharmacology. 2020;19:113-131.
  3. McPherson NO, Bell VG, Zander-Fox DL, et al. When two obese parents are worse than one! Impacts on embryo and fetal development. American journal of physiology Endocrinology and metabolism. 2015;309(6):E568-581.
  4. Wolodko K, Walewska E, Adamowski M, Castillo-Fernandez J, Kelsey G, Galvao A. Leptin Resistance in the Ovary of Obese Mice is Associated with Profound Changes in the Transcriptome of Cumulus Cells. Cell Physiol Biochem. 2020;54(3):417-437.
  5. Van de Pette M, Dimond A, Galvao AM, et al. Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice. Nat Commun. 2022;13(1):2464.