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Assisted reproduction causes placental maldevelopment and dysfunction linked to reduced fetal weight in mice.

ABSTRACT: Compelling evidence indicates that stress in utero, as manifested by low birth weight (LBW), increases the risk of metabolic syndrome in adulthood. Singletons conceived by assisted reproductive technology (ART) display a significant increase in LBW risk and ART offspring have a different metabolic profile starting at birth. Here, used mouse as a model, we found that ART resulted in reduced fetal weight and placental overgrowth at embryonic day 18.5 (E18.5). The ART placentae exhibited histomorphological alterations with defects in placental layer segregation and glycogen cells migration at E18.5. Further, ART treatments resulted in downregulation of a majority of placental nutrient transporters and reduction in placental efficiency. Moreover, the ART placentae were associated with increased methylation levels at imprinting control regions of H19, KvDMR1 and disrupted expression of a majority of imprinted genes important for placental development and function at E18.5. Our results from the mouse model show the first piece of evidence that ART treatment could affect fetal growth by disrupting placental development and function, suggests that perturbation of genomic imprinting resulted from embryo manipulation may contribute to these problems.

SUBMITTER: Chen S

PROVIDER: S-EPMC4471727 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Assisted reproduction causes placental maldevelopment and dysfunction linked to reduced fetal weight in mice.

Chen Shuqiang S Sun Fang-zhen FZ Huang Xiuying X Wang Xiaohong X Tang Na N Zhu Baoyi B Li Bo B

Scientific reports 20150618

Compelling evidence indicates that stress in utero, as manifested by low birth weight (LBW), increases the risk of metabolic syndrome in adulthood. Singletons conceived by assisted reproductive technology (ART) display a significant increase in LBW risk and ART offspring have a different metabolic profile starting at birth. Here, used mouse as a model, we found that ART resulted in reduced fetal weight and placental overgrowth at embryonic day 18.5 (E18.5). The ART placentae exhibited histomorph ...[more]

PMID: 26085229

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Project description:INTRODUCTION:Maternal-fetal chimerism is miniscule, a testament to the integrity of the uteroplacental interface. The soundness of this border region is potentially altered through cesarean delivery of prior babies with uncertain consequences for the following pregnancies. METHODS:Using multicolor flow cytometry and quantitative PCR of non-inherited maternal antigens we performed a retrospective case control pilot study and formulated the null hypothesis that placental implantation over a prior uterine scar does not result in the presence of memory Treg (CD45RO+) in the fetus. We then performed a power calculation and performed a blinded, appropriately powered prospective case control study to test the null hypothesis. RESULTS:Fetuses born to mothers with prior uterine scar have a roughly five times higher maternal to fetal microchimerism when the placenta directly interacts with the uterine scar. Unlike exposure to antigens in adult life, in utero antigenic exposure induces tolerogenic (Treg) responses in fetuses and we here report the presence of fetal Treg with a memory phenotype (CD45RO+). However, we only find such CD45RO+ fetal Tregs when the placenta abuts the uterine scar (Risk Ratio?=?5 [p?<?0.05 CI:(1.448 to 17.27)]). These memory fetal Tregs are functionally highly suppressive compared to CD45RA-expressing fetal Tregs, and have specificity for non-inherited maternal antigens. CONCLUSIONS:We found that uterine scars, in the case of our study these scars are from prior c-sections, fundamentally impair uterine integrity allowing for increased antigen exposure of the fetus; with our appropriately powered study we rejected the null hypothesis and accepted the alternative hypothesis that placental implantation over a prior uterine scar results in the presence of memory Treg (CD45RO+) in the fetus. Thus, our study demonstrates a previously unappreciated role for uterine integrity in limiting fetal antigenic exposure, a key element to avoid the formation of inappropriate tolerances by the fundamentally tolerogenic fetal immune system.

Dataset Information

Assisted reproduction causes placental maldevelopment and dysfunction linked to reduced fetal weight in mice.

Publications

Assisted reproduction causes placental maldevelopment and dysfunction linked to reduced fetal weight in mice.

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