In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men

Unusually large offspring have been born in ruminants following the transfer to recipients of embryos that have either been subjected to some form of manipulation, e.g. nuclear transfer, or have been exposed to an unusual in-vivo or in-vitro environment. Overgrowth syndromes have been reported in other species, including humans and mice, but these have arisen from chromosomal abnormalities and spontaneous or experimentally induced genetic mutations. Overgrowth phenotypes across the species, however, exhibit many common features, including alterations in organ and tissue development, and placental anomalies. Our current working hypothesis is that the causative agent(s) alter(s) the expression of a gene or genes associated with growth and development. Imprinted genes have been implicated in this syndrome because: (i) similar phenotypes are observed in both humans and mice when the expression of such genes has been altered; and (ii) they may be more vulnerable to epigenetic modification during the period (oocyte to blastocyst) when embryos are cultured in vitro. Evidence supporting this hypothesis is reviewed and the implications for assisted reproduction in humans discussed.