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The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model.

ABSTRACT: BACKGROUND:The fetal fraction of cell-free DNA (cfDNA) in maternal plasma is decreased in obese women. The underlying mechanism is not well understood. The amount of cfDNA released from the placenta has not been directly examined in maternal obesity. OBJECTIVE:We sought to quantify release of cfDNA from the placenta and fetal membranes in maternal diet-induced obesity using explant cultures in an established mouse model. STUDY DESIGN:C57BL6/J females were fed either 60% high-fat diet or 10% fat-matched control diet for 14 weeks prepregnancy and throughout gestation. Placentas and fetal membranes were collected on e18 and randomly allocated to time 0-, 1-, or 6-hour culture times. The CfDNA was isolated from culture media, quantified, and normalized to tissue weight. RESULTS:Placentas from obese dams released significantly less cfDNA compared to those of lean dams at time 0 (45.8 ± 4.3 ng/mg vs 65.6 ± 7.9 ng/mg, P = .02). Absolute cfDNA levels increased with longer placental culture, with no significant differences between obese and lean dams at 1 and 6 hours. Membranes released significantly less cfDNA than did placentas at every time point. CONCLUSIONS:Maternal obesity is associated with decreased release of cfDNA from the placenta compared to lean controls immediately after tissue harvest. This may provide an alternative explanation for the lower fetal fraction of cfDNA noted in maternal obesity.

SUBMITTER: Mhatre M

PROVIDER: S-EPMC6794655 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model.

Mhatre Mohak M Adeli Sharareh S Norwitz Errol E Craigo Sabrina S Phillippe Mark M Edlow Andrea A

Reproductive sciences (Thousand Oaks, Calif.) 20181119 9

<h4>Background</h4>The fetal fraction of cell-free DNA (cfDNA) in maternal plasma is decreased in obese women. The underlying mechanism is not well understood. The amount of cfDNA released from the placenta has not been directly examined in maternal obesity.<h4>Objective</h4>We sought to quantify release of cfDNA from the placenta and fetal membranes in maternal diet-induced obesity using explant cultures in an established mouse model.<h4>Study design</h4>C57BL6/J females were fed either 60% hig ...[more]

PMID: 30453834

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Project description:Does maternal obesity affect estrous cyclicity, embryo development and blastocyst gene expression in mice?Maternal obesity alters estrous cyclicity and causes the down-regulation of two key metabolite receptors (Slc2a1 and Ldlr) in blastocysts recovered from diet-induced obese females, but embryo development is not affected.Maternal obesity reduces fertility because of effects in the periconception period, but its negative influence is on estrous cyclicity, oocyte quality or embryo development.This was a randomized study based on a mouse model for obesity. Twenty-one outbred NIH Swiss mice were used and obesity was induced by a diet high in fat administered for 12 weeks prior to breeding to control males.Females were fed either a control diet (C, n = 9) or a diet high in fat [diet-induced obesity (DiO), n = 12] for 12 weeks, and were then co-housed with fertile males. Mice that failed to breed during 20 consecutive days were considered infertile. Control and diet-induced obese females that demonstrated vaginal plugs were euthanized 3.5 days after mating, blood was sampled for glucose and hormone measurements, corpora lutea counted and embryos recovered; the relative mRNA abundance of 11 candidate genes was determined in blastocysts by qPCR.Five DiO females failed to breed and displayed anovulatory ovaries (DiOI), whereas the other seven DiO females (DiOF) could breed, albeit over an extended period compared with controls. DiOF weighed significantly less than DiOI. Both groups had elevated serum insulin compared with C, although blood glucose level was only significantly higher than that in controls in the infertile DiOI group. Adiponectin was lower in the DiOI and leptin higher in both the DiOI and DiOF mice than in C. DiOF ovulated the same number of oocytes as C, and embryo development to blastocyst was normal. The expression of genes encoding metabolic hormone receptors (Insr, Igf1r, Igf2r, Adipor1, Adipor2 and Lepr) and key metabolic enzymes (Gapdh, Cpt1a and Sod2) did not differ between DiOF and C blastocysts, but that of metabolite receptors (Slc2a1 and Ldr) was down-regulated in DiOF. To limit the role of chance, the experiments were conducted in a defined laboratory setting with the proper controls, and the animals were randomly assigned to each experimental group. Moreover, a P-value of < 0.05 was chosen to determine whether the differences observed between the groups were statistically significant.The results obtained may not fully extrapolate to humans. Also, as follicular activity was not monitored while breeding, so the extended breeding period for DiOF group might be explained by behavioral abnormalities occurring in normal cycling animals.DiO alters the estrous cycle in the mouse model and demonstrates a role of obesity in infertility. The data also suggest that in an outbred, genetically diverse population, such as the human, individual susceptibility to obesity and associated infertility induced by diet exists. The apparently normal development to blastocyst observed in fertile, obese females suggests that preimplantation embryos can resist potentially adverse outcomes caused by an oversupply of fatty acids and glucose under in vivo conditions. This metabolic plasticity may, in part, be due to an ability to down-regulate metabolite transporters, thereby preventing excessive nutrient uptake.The research was supported by funds from the University of Missouri, grants from the National Institutes of Health and by a fellowship from the Lalor Foundation. There were no competing interests.Not applicable.

Dataset Information

The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model.

Publications

The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model.

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