In Vitro Fertilization Affects Growth and Glucose Metabolism in a Sex-Specific Manner in an Outbred Mouse Model1

Abstract

The preimplantation period is a time of reprogramming that may be vulnerable to disruption. This question has wide clinical relevance since the number of children conceived by in vitro fertilization (IVF) is rising. To examine this question, outbred mice (CF1 × B6D2F1) conceived by IVF and cultured using Whitten medium and 20% O2 (IVFWM group, less optimal) or K simplex optimized medium with amino acids and 5% O2 (IVFKAA group, more optimal and similar to conditions used in human IVF) were studied postnatally. We found that flushed blastocysts transferred to recipient mice provided the best control group (FB group), as this accounted for the effects of superovulation, embryo transfer, and litter size. We observed that many physiological parameters were normal. Reassuringly, IVFKAA offspring did not differ significantly from FB offspring. However, male IVFWM mice (but not females) were larger during the first 19 wk of life and exhibited glucose intolerance. Male IVFWM mice also showed enlarged left heart despite normal blood pressure. Expression of candidate imprinted genes (H19, Igf2, and Slc38a4) in multiple adult tissues did not show differences among the groups; only Slc38a4 was down-regulated following IVF (in both culture conditions) in female adipose tissue. These studies demonstrate that adult metabolism is affected by the type of conditions encountered during the preimplantation stage. Further, the postnatal growth trajectory and glucose homeostasis following ex vivo manipulation may be sexual dimorphic. Future work on the long-term effects of IVF offspring should focus on glucose metabolism and the cardiovascular system.

Oviduct: roles in fertilization and early embryo development

“…Yang and coworkers also found that cell death genes (BAX), antioxidant genes (MnSOD) and stress protective genes (HSP70) are elevated and apoptosis is increased in human embryos that were cultured at a 20% O 2 level . In addition, mouse embryos cultured in 20% O 2 showed pre-implantation epigenetic changes that altered metabolism later in life (Donjacour et al 2014). Specifically, male mice displayed glucose intolerance, heavier body weight and heart enlargement compared with in vivo fertilized embryos.…”

Effect of Vitrified Frozen-Thawed Embryo Transplantation on Glycometabolism of the Offspring Mice

“…Donjacur et al have detected the distribution of body lean and fat mass in IVF offspring by dual energy X-ray absorptiometry (DEXA) scanning, and found that the fat mass exhibits an obvious increase as the extension of age [5]. Similarly, Tamashiro et al have reported that the mice derived from in vitro cultured embryos have many obesity-associated characteristics [21].…”

“…Aberrant expression of imprinted genes has been observed on day 9.5 of the development after implantation of mouse embryos [3]. It has been reported that in vitro fertilization-embryo transfer (IVF-ET) manipulation was associated with low birth weight, Type-II diabetes, obesity, insulin resistance, [4,5]. However, the corresponding mechanisms leading to these issues are poorly known.…”

Postnatal consequences of assisted reproductive technologies in cattle

“…For example, fetal sex can affect milk yield in the existing lactation (Hinde et al, 2014) and it is conceivable that sex ratio of pregnancies in first lactation varied between groups. Given that culture system affected the nature of developmental programming in mice (Fernández-Gonzalez et al, 2004;Donjacour et al, 2014;, the effect of being born using a specific reproductive technology might depend on the particular details of the techniques employed. Accordingly, general conclusions should not be derived until the performance of animals derived from IVP or MOET is examined in a wide range of settings.…”

“…In one experiment, addition of serum to the medium of embryos cultured from the one-cell to blastocyst stages resulted in offspring with altered behavioral responses in males and females, increased adult weight in females at 31 weeks of age and later and increased liver and heart size in both sexes at 20 month of age (Fernández-Gonzalez et al, 2004). Using in vitro fertilization and embryo culture, Donjacour et al (2014) evaluated effect of embryo culture medium on properties of the resultant offspring. Culture media evaluated were KSOM and Whitten medium.…”