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.

Download Full-text

Beta-hydroxy-beta-methylbutyrate (HMB) Supplementation to Mouse Dams in Gestation Does Not Affect Fetal Weight Variation of Offspring or Placental Development (P09-003-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz033.p09-003-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Anna Clarke ◽

Nathan Horn ◽

Gerald Shurson ◽

Christopher Faulk ◽

Lee Johnston

Keyword(s):

Dietary Treatment ◽

Placental Weight ◽

Fetal Weight ◽

Placental Development ◽

Funding Sources ◽

Weight Variation ◽

Pulse Dose ◽

Pregnant Mice ◽

Placental Efficiency ◽

Dietary Treatments

Abstract Objectives The objective of this study was to determine if supplementing mouse dam diets with β-hydroxy-β-methylbutyrate (HMB) calcium salt throughout gestation would improve pup fetal weight uniformity and placental development. Methods Data were collected from 27 genetically identical mouse dams and their offspring. Dams were assigned to one of 4 dietary treatments: Control (CON; n = 7), Low HMB (LHMB; 3.5 mg/g diet; n = 6), High HMB (HHMB; 35 mg/g diet; n = 7), and low HMB pulse dose (PUL; 3.5 mg/g diet; n = 7) from days 6 to 10 of gestation. All dams were fed a swine lactation derived corn-soy diet with HMB supplementation only during gestation. Dams were euthanized on day 18 of gestation. Results Dietary treatment did not affect total number of pups per litter, but fetal weight was greater (P < 0.05) for pups from PUL dams (1.05 ± 0.02 g) than LHMB (0.94 ± 0.02 g) or HHMB (0.95 ± 0.02 g) dams. Within-litter variation (standard deviation and coefficient of variation) and range of fetal weights was not different among treatments. Differences between the median fetal weight within litter and weight of the lowest weight fetal pup in each litter were similar among treatments. Supplementation with HMB did not influence weight of placentae or area of the placental labyrinth. Placental efficiency, measured as fetal weight/placental weight, was less (P < 0.05) for LHMB dams compared to CON dams. Conclusions In conclusion, dietary supplementation of HMB for pregnant mice had no effect on fetal weight variation within litter. Supplementing diets with β-hydroxy-β-methylbutyrate had no effect on placental weight or labyrinth area but reduced placental efficiency in dams fed LHMB. Funding Sources This research has been supported and funded by BioMatrix International, Princeton, MN.

Download Full-text

Breed and parity differences in ovine placentation: Implications for placental efficiency and lamb vigour

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200011649 ◽

2003 ◽

Vol 2003 ◽

pp. 5-5

Author(s):

C. M. Dwyer ◽

S. K. Calvert ◽

M. Farish ◽

S. Cotham ◽

J. Donbavand ◽

...

Keyword(s):

Litter Size ◽

Maternal Factors ◽

Behavioural Development ◽

Placental Development ◽

Lamb Survival ◽

Placental Efficiency ◽

And Function

Lamb vigour at birth (i.e. time to stand after delivery) is known to be affected by a number of maternal factors, such as parity and litter size (Dwyer, 2002), as well as lamb breed (Dwyer et al., 1996), and is related to subsequent lamb survival (Dwyer et al., 2001). It is likely that these factors act before birth to influence lamb development and may exert their effects through differences in placental development and function. The purpose of this experiment was to examine the effects of ewe parity, litter size and ewe breed on placental components, and relate these to lamb behavioural development at birth.

Download Full-text

SUN-552 Follistatin-Like 3 (FSTL3), a Transforming Growth Factor β (TGFβ) Ligand Inhibitor, Regulates Placental Development in Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1819 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Josef Huntington ◽

Rachel Robertson ◽

Gurtej K Dhoot ◽

Imelda M McGonnell ◽

Caroline Wheeler-Jones ◽

...

Keyword(s):

Growth Factor ◽

Cellular Proliferation ◽

Transforming Growth Factor ◽

Expression Patterns ◽

Transforming Growth Factor Β ◽

Placental Development ◽

Matrix Deposition ◽

Smad2 Phosphorylation ◽

Placental Efficiency ◽

And Function

Abstract Follistatin-like 3 (FSTL3), a glycoprotein that inhibits transforming growth factor-β (TGFβ) ligands such as activin, is expressed highly in the placenta and other vascular tissues. In addition, FSTL3 is strongly induced in pre-eclamptic placenta. To test the hypothesis that FSTL3 function is required for capillary bed structure and function we studied the placenta in FSTL3 gene deleted mice (FSTL3 KO). We have previously shown that FSTL3 deletion produces striking defects in the placenta when compared to WT. Placental size increases significantly in comparison to WT, at 16.5 and 18.5 dpc, with concurrent reduction in placental efficiency at 18.5 dpc. Histological analyses reveal structural differences in placental junctional zones in FSTL3 KO placenta compared to WT. Morphometric analyses show that the labyrinth area compared to the placenta area is significantly reduced in FSTL3 KO mice. We also found that activin-responsive FSTL3-synexpression genes are upregulated in FSTL3 KO placenta. Of these, EPHB4 protein is induced in the placenta along with its ligand EphrinB2. Here we show that FSTL3 deletion leads to endothelial cell expansion but reduction in blood vessel density along with increased extracellular matrix deposition. Further investigation of the placental phenotype revealed differential expression patterns of desmin and cytokeratin protein, reduced von Willebrand factor (VWF) and increased CD31 and VEGFR2 labelling within FSTL3 KO mice placental labyrinths. To identify mechanisms that might lead to the altered placental development in FSTL3 KO mice qPCR analyses were performed. Our results identified differences in the expression of crucial transcripts, such as Cdh5, Pgf, Fra1and Cited1, that are associated with the regulation of vascular biology. Additionally, we find increased Histone3 and SMAD2 phosphorylation in FSTL3 KO placenta indicating increased proliferation and activin signalling, respectively. These findings suggest that the balance between cellular proliferation and differentiation might be altered in the absence of FSTL3. Thus, we conclude that FSTL3 function, at least partly through the inhibition of activin action, is necessary for normal placental circulation and development.

Download Full-text

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

Reproduction ◽

10.1530/rep-08-0516 ◽

2009 ◽

Vol 137 (4) ◽

pp. 749-757 ◽

Cited By ~ 40

Author(s):

Dale A Redmer ◽

Justin S Luther ◽

John S Milne ◽

Raymond P Aitken ◽

Mary Lynn Johnson ◽

...

Keyword(s):

Vascular Development ◽

Nutrient Supply ◽

Late Gestation ◽

Fetal Weight ◽

Dietary Intakes ◽

Subsequent Reduction ◽

Placental Development ◽

Three Stages ◽

And Function ◽

Singleton Pregnancies

To establish the basis for altered placental development and function previously observed at late gestation, fetoplacental growth and placental vascular development were measured at three stages of gestation in a nutritional paradigm of compromised pregnancy. Singleton pregnancies to a single sire were established and thereafter adolescent ewes were offered an optimal control (C) or a high (H) dietary intake. At day 50, the H group had elevated maternal insulin and amniotic glucose, whereas mass of the fetus and placenta were unaltered. At day 90, the H group exhibited elevated maternal insulin, IGF1 and glucose; fetal weight and glucose concentrations in H were increased relative to C, but placental weight was independent of nutrition. By day 130, total placentome weight in the H group was reduced by 46% and was associated with lower fetal glucose and a 20% reduction in fetal weight. As pregnancy progressed from day 50 to 130, the parameters of vascular development in the maternal and fetal components of the placenta increased. In the fetal cotyledon, high dietary intakes were associated with impaired vascular development at day 50 and an increase in capillary number at day 90. At day 130, all vascular indices were independent of nutrition. Thus, high dietary intakes to promote rapid maternal growth influence capillary development in the fetal portion of the placenta during early to mid-pregnancy and may underlie the subsequent reduction in placental mass and hence fetal nutrient supply observed during the final third of gestation.

Download Full-text

Effect of Different Components of Metabolic Syndrome on Right Ventricular Volume and Function

Zagazig University Medical Journal ◽

10.21608/zumj.2019.17903.1575 ◽

2019 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

Abdosalam attaleb ◽

Mahmoud El-Menshawy ◽

Mohammad AL-Daydamony ◽

Ahmed El-damanhory

Keyword(s):

Metabolic Syndrome ◽

Right Ventricular ◽

Ventricular Volume ◽

Right Ventricular Volume ◽

And Function

Download Full-text

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

Download Full-text

A Potential Role and Contribution of Androgens in Placental Development and Pregnancy

Life ◽

10.3390/life11070644 ◽

2021 ◽

Vol 11 (7) ◽

pp. 644

Author(s):

Agata M. Parsons ◽

Gerrit J. Bouma

Keyword(s):

Fetal Development ◽

Fetal Loss ◽

Membrane Receptors ◽

Placental Development ◽

Placental Function ◽

Fetal Physiology ◽

Estrogen Synthesis ◽

And Function ◽

Pregnancy Disorders

Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.

Download Full-text

Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽

10.3390/mi12080884 ◽

2021 ◽

Vol 12 (8) ◽

pp. 884

Author(s):

Marta Cherubini ◽

Scott Erickson ◽

Kristina Haase

Keyword(s):

Drug Testing ◽

Cell Types ◽

In Vitro Models ◽

Placental Development ◽

Scientific Challenge ◽

Induced Pluripotent ◽

And Function ◽

And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

Download Full-text

Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging

Biology ◽

10.3390/biology10040253 ◽

2021 ◽

Vol 10 (4) ◽

pp. 253

Author(s):

Graciela Gavia-García ◽

Juana Rosado-Pérez ◽

Taide Laurita Arista-Ugalde ◽

Itzen Aguiñiga-Sánchez ◽

Edelmiro Santiago-Osorio ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Telomere Length ◽

Scientific Evidence ◽

Telomeric Dna ◽

Biochemical Alterations ◽

The Metabolic Syndrome ◽

Age Related ◽

And Function

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

Download Full-text

The Potential Applications of Peroxisome Proliferator-Activated ReceptorδLigands in Assisted Reproductive Technology

PPAR Research ◽

10.1155/2008/794814 ◽

2008 ◽

Vol 2008 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Jaou-Chen Huang

Keyword(s):

Assisted Reproductive Technology ◽

Reproductive Function ◽

Reproductive Technology ◽

Embryonic Cell ◽

Preimplantation Embryos ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Potential Applications ◽

And Function

Peroxisome proliferator-activated receptorδ(PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδwas first revealed in the uterus at the implantation site. Since then, PPARδand its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδin preimplantation embryos is normally activated by oviduct-derived PPARδligand. PPARδactivation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδand its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδand project its potential applications in assisted reproductive technology.

Download Full-text