Dexamethasone treatment of pregnant F0 mice leads to parent of origin-specific changes in placental function of the F2 generation.

Dexamethasone treatment of F0 pregnant rodents alters F1 placental function and adult cardiometabolic phenotype. The adult phenotype is transmitted to the F2 generation without further intervention, but whether F2 placental function is altered by F0 dexamethasone treatment remains unknown. In the present study, F0 mice were untreated or received dexamethasone (0.2µgg(-1)day(-1), s.c.) over Days 11-15 or 14-18 of pregnancy (term Day 21). Depending on the period of F0 dexamethasone treatment, F1 offspring were lighter at birth or grew more slowly until weaning (P<0.05). Glucose tolerance (1gkg(-1), i.p.) of adult F1 males was abnormal. Mating F1 males exposed prenatally to dexamethasone with untreated females had no effect on F2 placental function on Day 19 of pregnancy. In contrast, when F1 females were mated with untreated males, F2 placental clearance of the amino acid analogue (14)C-methylaminoisobutyric acid was increased by 75% on Day 19 specifically in dams prenatally exposed to dexamethasone on Days 14-18 (P<0.05). Maternal plasma corticosterone was also increased, but F2 placental Slc38a4 expression was decreased in these dams (P<0.05). F0 dexamethasone treatment had no effect on F2 fetal or placental weights, regardless of lineage. Therefore, the effects of F0 dexamethasone exposure are transmitted intergenerationally to the F2 placenta via the maternal, but not paternal, line.This is the accepted manuscript. The final version is available at http://dx.doi.org/10.1071/RD14285

Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft.

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/JP27200

A Western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice

In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy. However, the impacts of a HFHS diet during pregnancy on maternal insulin sensitivity and signalling in relation to feto-placental growth and glucose utilization are unknown. The present study examined the effects of a HFHS diet during mouse pregnancy on maternal glucose tolerance and insulin resistance, as well as, on feto-placental glucose metabolism. Female mice were fed a control or HFHS diet from day (D) 1 of pregnancy (term = D20.5). At D16 or D19, dams were assessed for body composition, metabolite and hormone concentrations, tissue abundance of growth and metabolic signalling pathways, glucose tolerance and utilization and insulin sensitivity. HFHS feeding perturbed maternal insulin sensitivity in late pregnancy; hepatic insulin sensitivity was higher, whereas sensitivity of the skeletal muscle and white adipose tissue was lower in HFHS than control dams. These changes were accompanied by increased adiposity and reduced glucose production and glucose tolerance of HFHS dams. The HFHS diet also disturbed the hormone and metabolite milieu and altered expression of growth and metabolic signalling pathways in maternal tissues. Furthermore, HFHS feeding was associated with impaired feto-placental glucose metabolism and growth. A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth. These findings have implications for the health of women and their infants, who consume HFHS diets during pregnancy.We are grateful to the Medical Research Council (MRC) for funding the research through a studentship to BM (MR/J500458/1), an in vivo skills award (MRC CORD G0600717) and the MRC Metabolic Diseases Unit (MC_UU_12012/4)

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4$^{+}$ T cells displaying a GARP$^{+}$CD127$^{Io}$FOXP3$^{+}$ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil-T cell interactions in the regulation of vascularization at the maternal-fetal interface.S.N. and M.P. were supported by the Wellcome Trust (Programme 086867/Z/08/Z). F.M.M.-B. is supported by the British Heart Foundation (CH/15/2/32064). D.J.W. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. S.H.P.F. is a Research Fellow at CNPq. This work is part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institutes of Health Research

PAPP-A2 Deficiency Does Not Exacerbate the Phenotype of a Mouse Model of Intrauterine Growth Restriction

BACKGROUND: Pregnancy-associated plasma protein-A2 (PAPP-A2) is consistently upregulated in the placentae of pregnancies complicated by preeclampsia and fetal growth restriction. The causes and significance of this upregulation remain unknown, but it has been hypothesized that it is a compensatory response to improve placental growth and development. We predicted that, if the upregulation of PAPP-A2 in pregnancy complications reflects a compensatory response, then deletion of Pappa2 in mice would exacerbate the effects of a gene deletion previously reported to impair placental development: deficiency of matrix metalloproteinase-9 (MMP9). METHODS: We crossed mice carrying deletions in Pappa2 and Mmp9 to produce pregnancies deficient in one, both, or neither of these genes. We measured pregnancy rates, number of conceptuses, fetal and placental growth, and the histological structure of the placenta. RESULTS: We found no evidence of reduced fertility, increased pregnancy loss, or increased fetal demise in Mmp9&nbsp;-/-&nbsp;females. In pregnancies segregating for Mmp9, Mmp9&nbsp;-/-&nbsp;fetuses were lighter than their siblings with a functional Mmp9 allele. However, deletion of Pappa2 did not exacerbate or reveal any effects of Mmp9 deficiency. We observed some effects of Pappa2 deletion on placental structure that were independent of Mmp9 deficiency, but no effects on fetal growth. At G16, male fetuses were heavier than female fetuses and had heavier placentae with larger junctional zones and smaller labyrinths. CONCLUSIONS: Effects of Mmp9 deficiency were not exacerbated by the deletion of Pappa2. Our results do not provide evidence that upregulation of placental PAPP-A2 represents a mechanism to compensate for impaired fetal growth. &nbsp

A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects

Mammals have three HP1 protein isotypes HP1β (CBX1), HP1γ (CBX3) and HP1α (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3 hypo) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3 hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3 hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3 hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3 hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the Cbx3 hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality