Impaired Placental Nutrient Transport in Mice Generated by in Vitro Fertilization

Abstract

More than 4.5 million children have been conceived by in vitro fertilization (IVF). Interestingly, singleton IVF offspring born at term have an increased incidence of low birth weight. The mechanism responsible for the lower birth weight is unknown, but alterations in placental function are possible. Hence, the goal of our study was to examine placental growth and function in mice generated in vivo or in vitro. To assess placental function, blastocysts were generated by IVF or produced by natural mating (control group); both IVF and control blastocysts were transferred to pseudopregnant recipients. Placental weights did not differ at embryonic d 15.5 (E15.5) but were increased at E18.5 in the IVF group (25.4%, P < 0.001) compared with control. Proliferation was increased in IVF placentae, whereas overall placental gross morphology and apoptosis were not affected. Both fetal weights (16.4% lower at E15.5 and 8.8% lower at E18.5, P < 0.05) and fetal to placental ratios were lower (P < 0.001) in the IVF compared with the control group at both time points, whereas birth weights did not differ. At E18.5, the mRNA for selected glucose, system A amino acid transporters, and imprinted genes were down-regulated in IVF placentae. GLUT3 protein level was decreased in the IVF group (P < 0.05). Importantly, intrajugular injections of (14)C-methyl-D-glucose or (14)C-MeAIB tracers (n = 6 litters per group) showed that placental transport of glucose and amino acids were 24.8% (not significant) and 58.1% (P < 0.05) lower in the IVF group. Fetal accumulation of glucose was not different, but amino acid accumulation was significantly (36 %) lower in IVF fetuses (P < 0.05). We conclude that IVF alters both fetal and placental growth and, importantly, decreases placental transport efficiency in mice conceived by IVF.

IVF affects embryonic development in a sex-biased manner in mice

“…This phenomenon, that the differences in fetal weight observed at E13.5 disappear 6 days later (at E19.5), is in accordance with that reported by previous study (Bloise et al 2012), in which the relative IVF fetal weight to IVO controls is lowest at the mid-gestation stage. After that, differences in fetal weight between IVF and IVO embryos reduce gradually until they disappear.…”

“…After that, differences in fetal weight between IVF and IVO embryos reduce gradually until they disappear. One plausible explanation is the compensatory effect due to the larger placentas in IVF groups compared with that in control groups (Bloise et al 2012). Indeed, we found evident placental overgrowth in IVF males and females.…”

Behavior and Brain Gene Expression Changes in Mice Exposed to Preimplantation and Prenatal Stress

“…Oocytes were obtained from superovulated C57Bl/ 6J female mice as described previously. 14,25 Briefly, female mice were injected with 5 IU of pregnant mare serum gonadotropin and 46 to 48 hours later with 5 IU of human chorionic gonadotropin (hCG). The following morning, oocytes were collected from the ampullae.…”

“…Several studies in humans and animals have shown that in vitro fertilization (IVF) and embryo culture can be metabolically taxing on preimplantation embryos. Indeed, oxidative stress can have a considerable impact on embryo development and cultured preimplantation embryos show metabolic changes, 11 abnormal metabolic and ultrastructural configurations, 12 increased programmed cell death in cells in the inner cell mass, 13 abnormalities of placentation, 14 and altered expression of developmentally important genes. [15][16][17][18][19] Culture media and/or nonphysiological oxygen tension contribute to these adaptive changes to increased oxidative stress.…”

The Effects of Maternal Periconceptional Ethanol Exposure on the Development of the Pre-Implantation Embryo, Placenta, and the Influence of the Uterine Environment

“…This includes the periconceptional period, in which alterations to the trophectoderm, the progenitor pool to the placenta, can influence placentation days after the initial exposure (Kwong et al, 2000, Watkins et al, 2015, MacLaughlin et al, 2005, Tan et al, 2016a, Bloise et al, 2012. The placenta also can mediate sexually dimorphic outcomes, with perturbations in early development associated with female lethality (Tan et al, 2016b), while mid-late gestational exposures are largely associated with male-specific lethality (reviewed by Kalisch-Smith et al 2017a).…”