scholarly journals Male Fetal Sex Affects Uteroplacental Angiogenesis in Growth Restriction Mouse Model†

2021 ◽  
Author(s):  
Jessica F Hebert ◽  
Jess A Millar ◽  
Rahul Raghavan ◽  
Amie Romney ◽  
Jason E Podrabsky ◽  
...  
Keyword(s):  
Mouse Model ◽  
Killer Cell ◽  
Receptor Activation ◽  
Growth Restriction ◽  
Late Gestation ◽  
Spiral Artery ◽  
Micro Computed Tomography ◽  
Fetal Sex ◽  
Maternal Genotype ◽  
Agt Gene

Abstract Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age (SGA) babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[−6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer cell (uNK) phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional micro-computed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.

scholarly journals DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure

Epigenetics ◽  
2017 ◽  
Vol 12 (10) ◽  
pp. 841-853 ◽  
Author(s):  
Richard C. Chang ◽  
William M. Skiles ◽  
Sarah S. Chronister ◽  
Haiqing Wang ◽  
Gabrielle I. Sutton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mouse Model ◽  
Alcohol Exposure ◽  
Developmental Programming ◽  
Growth Restriction

scholarly journals A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance

2020 ◽  
Vol 29 (13) ◽  
pp. 2171-2184
Author(s):  
Bridget M Stroup ◽  
Ronit Marom ◽  
Xiaohui Li ◽  
Chih-Wei Hsu ◽  
Cheng-Yen Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Knockout Mouse ◽  
Skeletal Development ◽  
Growth Failure ◽  
Tubular Dysfunction ◽  
Micro Computed Tomography ◽  
Lysinuric Protein Intolerance ◽  
Knockout Mouse Model ◽  
Lysinuric Protein ◽  
Protein Intolerance

Abstract Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

Double resin casting micro computed tomography (CT) reveals biliary and vascular pathology in tandem in a mouse model for alagille syndrome

2020 ◽  
Vol 73 ◽  
pp. S43
Author(s):  
Simona Hankeova ◽  
Jakub Salplachta ◽  
Tomas Zikmund ◽  
Michaela Kavkova ◽  
Noémi K.M. Van Hul ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Mouse Model ◽  
Alagille Syndrome ◽  
Vascular Pathology ◽  
Micro Computed Tomography

scholarly journals Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

2014 ◽  
Vol 22 (10) ◽  
pp. 1172-1179 ◽  
Author(s):  
Manshu Tang ◽  
Anwer Siddiqi ◽  
Benjamin Witt ◽  
Tatiana Yuzyuk ◽  
Britt Johnson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Growth Restriction ◽  
Deficient Mouse

scholarly journals Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels

2002 ◽  
Vol 174 (1) ◽  
pp. 37-43 ◽  
Author(s):  
J Lesage ◽  
D Hahn ◽  
M Leonhardt ◽  
B Blondeau ◽  
B Breant ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Glucose ◽  
Food Restriction ◽  
Glucose Transporter ◽  
Maternal Plasma ◽  
Plasma Corticosterone ◽  
Growth Restriction ◽  
Late Gestation ◽  
Glucose Content ◽  
Protein Levels

Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels. At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0.05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0.001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0.05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0.001) but higher plasma corticosterone levels (P<0.05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0.01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0.01) and in pups from ADX control mothers (P<0.01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0.05 and P<0.01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery. We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.

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