Establishment of early pregnancy Short lay paragraph

Improving superovulation and pregnancy rates in laboratory rodents.

Rationale

In 2017, 1.9 million animals were used in the creation/breeding of genetically altered (GA) animals, an increase of 37% in the last decade. This trend, which appears set to continue, is largely attributable to advances in gene editing technology.

GA animals are created by transferring gene-edited embryos surgically into surrogate mothers. These embryos are originally obtained from female animals in which production of eggs in ovaries is artificially increased using drugs given by injection ('superovulation'). Embryos only implant into the uterus of surrogate mothers if the latter experience false pregnancies ('pseudopregnancy'), a process achieved by mating them to infertile males.

This mating process exposes the maternal reproductive tract to sperm-free ejaculates which 'prime' the uterus to receive the embryo. These males are housed in isolation to prevent them from fighting and are typically rendered infertile through surgical vasectomy, both of which raise major welfare concerns.

Moreover, females caged with these males for mating do not always willingly accept their advances if they are not sexually receptive. This makes such mating encounters stressful and/or unsuccessful, and results in twice as many females being mated relative to those required for embryo surrogacy.

This study builds on our pioneering work in the area and focuses on replacing sterile males, refining/reducing the severity of superovulation regimes and enhancing pregnancy rates, thereby minimising animal wastage and improving welfare in laboratory rodents. This project will also greatly improve our understanding of the biological mechanisms involved in the establishment of pregnancy.

Summary

Female mice will be superovulated using minimally invasive approaches (donors). Others (recipients) will be rendered pseudopregnant by using sterile males or synthetic pessaries.

Animal care and welfare

Animals will be housed in cages with environmental enrichment (nesting material, dome) appropriate to their size/numbers with unlimited access to food/water. All will be visually checked daily.

Any welfare issues will be promptly resolved (with veterinary surgeon input if needed). Females may experience minor pain due to hormone injections, whilst their counterparts undergoing surgery (vasectomy, embryo transfer) will be given pain relief to minimise discomfort.

3R’s

Replacement: Cannot replace animals due to the complexity of pregnancy physiology.
Reduction: Statistical input will minimise animal usage whilst supporting scientifically valid conclusions.
Refinement: Using robust mouse strains with excellent mothering abilities will improve foetal/neonatal development. Techniques will be performed by experienced staff trained in the latest surgical methods.

Scientific advancement

This project will enhance reproductive performance in laboratory rodents and have a positive impact on animal welfare and the 3R's globally. Successful findings will be translated to domestic livestock reproduction and human fertility treatment.

Non-technical summary

Read Establishment of early pregnancy non-technical summary (PDF).

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