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. 2014 Feb 13;90(2):26.
doi: 10.1095/biolreprod.113.110411. Print 2014 Feb.

Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth

Monica A Mainigi  1 , Devvora Olalere, Irina Burd, Carmen Sapienza, Marisa Bartolomei, Christos Coutifaris
Affiliations

Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth

Monica A Mainigi et al. Biol Reprod. .

Abstract

Assisted reproductive technologies (ART) have been associated with several adverse perinatal outcomes involving placentation and fetal growth. It is critical to examine each intervention individually in order to assess its relationship to the described adverse perinatal outcomes. One intervention ubiquitously used in ART is superovulation with gonadotropins. Superovulation results in significant changes in the hormonal milieu, which persist during the peri-implantation and early placentation periods. Epidemiologic evidence suggests that the treatment-induced peri-implantation maternal environment plays a critical role in perinatal outcomes. In this study, using the mouse model, we have isolated the exposure to the peri-implantation period, and we examine the effect of superovulation on placentation and fetal growth. We report that the nonphysiologic peri-implantation maternal hormonal environment resulting from gonadotropin stimulation appears to have a direct effect on fetal growth, trophoblast differentiation, and gene expression. This appears to be mediated, at least in part, through trophoblast expansion and invasion. Although the specific molecular and cellular mechanism(s) leading to these observations remain to be elucidated, identifying this modifiable risk factor will not only allow us to improve perinatal outcomes with ART, but help us understand the pathophysiology contributing to these outcomes.

Keywords: ART; epigenetics; estradiol; gonadotropins; implantation.

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Figures

FIG. 1
FIG. 1
Serum hormone levels in mice following natural mating (white bar) or mating following superovulation with gonadotropins (black bar). A) Serum estradiol levels were significantly elevated in those mice treated with gonadotropins compared to controls on the day of mating. However, by Postcoital Day 4, estradiol levels had returned to baseline. B) VEGF levels were significantly elevated following superovulation when compared to controls, and this elevation persisted into the peri-implantation period. aP < 0.05 versus natural mating. Data are expressed as mean ± SEM.
FIG. 2
FIG. 2
Five control (white bars) and eight SO dams (black bars) were sacrificed at E18.5. A) Mean litter size was not different between the groups. Fetal weights (B) and placental weights (C) were significantly different between the two groups, regardless of sex of the offspring (D, E) (control: n = 16, 7 female, 9 male; SO: n = 23, 7 female, 16 male). F) Fetus to placenta weight ratio was not different between the groups. aP < 0.05 versus natural mating (each sex compared to offspring of the same sex). bP < 0.001 versus natural mating. Data are expressed as mean ± SEM.
FIG. 3
FIG. 3
Histopathological examination of placentas from control and SO recipients. A) Placentas from SO recipients (black bar) demonstrated a reduced junctional to labyrinth zone ratio compared to placentas from control recipients (white bar) (n = 10 control, 5 male, 5 female; n = 20 SO, 12 male, 8 female). B) Placentas from SO recipients showed attenuated branching with limited invasion of the junctional zone by the labyrinth. C) Placental expression of selected markers of different placental cell types in SO recipients (black bar) and control recipients (white bar). aP < 0.05 versus natural mating. Data are expressed as mean ± SEM. Original magnification ×2.5.
FIG. 4
FIG. 4
Placental expression of Grb10 was elevated in placentas obtained from SO recipients (black bar) compared to control recipients (white bar) though expression of other growth-related genes did not differ between the two groups (A–D). Gene expression of Grb10, Igf2, Igf2r, and H19 did not differ in the liver (E–H) or other embryonic tissues (data not shown). Gene expression was measured by qRT-PCR at E18.5. Fold change values for each time point are relative to control and normalized to Rplpo. At least eight placentas were examined in each group, four males and four females. aP < 0.05. Data are expressed as mean ± SEM.
FIG. 5
FIG. 5
A) Immunohistochemistry using an antibody to GRB10 shows GRB10 expression primarily in the labyrinth zone of the placenta, with increased expression in the SO placenta. B) Western blot analysis of protein lysates from E18.5 placenta from control or SO recipients with an antibody against the C terminus of GRB10. An anti-actin antibody was used as a loading control. (Representative images, eight placenta examined in each group.) Original magnification ×40.
FIG. 6
FIG. 6
DNA methylation at the differentially methylated region of six imprinted genes thought to be affected by ART (A–F). Pyrosequencing found no difference in mean DNA methylation at these sites in placental tissue from control (white bars) and SO placentas (black bars). G) There was also no difference in global methylation in the placenta between the two groups. At least eight placentas were examined in each group, four males and four females. Data are expressed as mean ± SEM.
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