Placental invasiveness and brain-body allometry in eutherian mammals

Brain growth is a key trait in the evolution of mammalian life history. Brain development should be mediated by placentation, which determines patterns of resource transfer from mothers to fetal offspring. Eutherian placentation varies in the extent to which a maternal barrier separates fetal tissues from maternal blood. We demonstrate here that more invasive forms of placentation are associated with substantially steeper brain-body allometry, faster prenatal brain growth and slower prenatal body growth. On the basis of the physiological literature we suggest a simple mechanism for these differences: in species with invasive placentation, where the placenta is bathed directly in maternal blood, fatty acids essential for brain development can be readily extracted by the fetus, but in species with less invasive placentation they must be synthesized by the fetus. Hence, with regard to brain-body allometry and prenatal growth patterns, eutherian mammals are structured into distinct groups differing in placental invasiveness.     

Deleterious effects of polynuclear aromatic hydrocarbon on blood vascular system of the rat fetus

BACKGROUND: Polynuclear aromatic hydrocarbons (PAH), benzo[alpha]pyrene (B[alpha]P) and 7,12-dimethylbenz[alpha]anthracene (DMBA) are toxic environmental agents distributed widely. The relative deleterious effects of these agents on growth and blood vasculature of fetus and placental tissues of the rat were studied. METHODS: Pregnant rats (Day 1 sperm positive) with implantation sites confirmed by laparotomy were treated intraperitoneally (i.p.) on Pregnancy Days 10, 12, and 14 with these agents dissolved in corn oil at cumulated total doses 50, 100, and 200 mg/kg/rat, and control with corn oil only (3-20 dams/group). Fetal growth, tissue hemorrhage, and placental pathology were evaluated by different parameters on Pregnancy Day (PD) 20 in treated and control rats. RESULTS: DMBA was relatively more deleterious compared to B[alpha]P indicated by increased lethality and progressive reduction of body weight of the mother with increasing doses. At 200 mg/kg/rat doses of these agents, maternal survival was 45% and 100% and body weight reduced 24% and 52% of controls, respectively. The fetal survival rates in live mothers were similar to that of controls. They induced marked fetal growth retardation and necrosis of placental tissues. B[alpha]P and DMBA produced significant toxicity to differentiating fetal blood vascular system as exhibited by rupture of blood vessels and hemorrhage, especially in the skin, cranial, and brain tissues. CONCLUSIONS: Maternal PAH exposure induced placental toxicity and associated adverse fetal development and hemorrhage in different parts of the fetal body, in particular, marked intradermal and cranial hemorrhage, showing that developing fetal blood vasculature is a target of PAH toxicity.     

Placental efficiency and intrauterine resource allocation strategies in the common marmoset pregnancy

Mothers and fetuses are expected to be in some degree of conflict over the allocation of maternal resources to fetal growth in the intrauterine environment. Variation in placental structure and function may be one way a fetus can communicate need and quality to its mother, potentially manipulating maternal investment in its favor. Whereas common marmosets typically produce twin litters, they regularly give birth to triplet litters in captivity. The addition of another fetus is a potential drain on maternal resource availability and thus a source of elevated conflict over resource allocation. Marmoset littermates share a single placental mass, so that differences in the ratio of fetal to placental weight across litter categories suggest the presence of differential intrauterine strategies of resource allocation. The fetal/placental weight ratio was calculated for 26 marmoset pregnancies, representing both twin and triplet litters, to test the hypothesis that triplet fetuses respond to intrauterine conflict by soliciting placental overgrowth as a means of accessing maternal resources. In fact, relative to fetal mass, the triplet marmoset placenta is significantly undergrown, with individual triplets associated with less placental mass than their twin counterparts, suggesting that the triplet placenta is relatively more efficient in its support of fetal growth. There still may be an important role for maternal-fetal conflict in the programming of placental structure and function. Placental adaptations that solicit potential increases of maternal investment may occur at the microscopic or metabolic level, and thus may not be reflected in the size of the placenta as a whole.     

Sex-specific responses in placental fatty acid oxidation,esterification and transfer capacity to maternal obesity

Fatty acid metabolism and oxidation capacity in the placenta, which likely affects the rate and composition of lipid delivered to the fetus remains poorly understood. Long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), are critical for fetal growth and brain development. We determined the impact of maternal obesity on placental fatty acid oxidation, esterification and transport capacity by measuring PhosphatidylCholine (PC) and LysoPhosphatidylCholine (LPC) containing DHA by mass spectrometry in mother-placenta-baby triads as well as placental free carnitine and acylcarnitine metabolites in women with normal and obese pre-pregnancy BMI. Placental protein expression of enzymes involved in beta-oxidation and esterification pathways, MFSD2a (lysophosphatidylcholine transporter) and OCTN2 (carnitine transporter) expression in syncytiotrophoblast microvillous (MVM) and basal (BM) membranes were determined by Western Blot. Maternal obesity was associated with decreased umbilical cord plasma DHA in LPC and PC fractions in male, but not female, fetuses. Basal membrane MFSD2a protein expression was increased in placenta of males of obese mothers. In female placentas, despite an increased MVM OCTN2 expression, maternal obesity was associated with a reduced MUFA-carnitine levels and increased esterification enzymes. We speculate that lower DHA-PL in fetal circulation of male offspring of obese mothers, despite a significant increase in transporter expression for LPC-DHA, may lead to low DHA needed for brain development contributing to neurological consequences that are more prevalent in male children. Female placentas likely have reduced beta-oxidation capacity and appear to store FA through greater placental esterification, suggesting impaired placenta function and lipid transfer in female placentas of obese mothers.     

Fetal Liver Blood Flow Distribution: Role in Human Developmental Strategy to Prioritize Fat Deposition versus Brain Development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother''s adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.     

Evolution of Placentation in Primates: Implications of Mammalian Phylogeny

Primates are quite unique among placental mammals in that the two extreme types of placentation are present within a single order. Strepsirrhines (lemurs and lorisiforms) have non-invasive epitheliochorial placentation, whereas haplorhines (tarsiers and higher primates) have highly invasive haemochorial placentation. Resemblance in placenta type in fact provided the first evidence that tarsiers are linked to higher primates and distinct from lemurs and lorisiforms. Tree-shrews differ from both primate subgroups in having moderately invasive endotheliochorial placentation, while colugos have invasive haemochorial placentation like haplorhines. All three kinds of placentation have been identified as primitive for placentals by different authors, but until recently the prevailing interpretation has been that non-invasive epitheliochorial placentation is primitive and “less efficient”. Opposing this interpretation, Martin (Primate origins and evolution: a phylogenetic reconstruction, 1990) proposed that moderately invasive endotheliochorial placentation is primitive. Epitheliochorial placentation is unlikely to be primitive because it is predominantly associated with large body size, relatively long gestation periods and precocial offspring. Furthermore, some strepsirrhines and other placental mammals with epitheliochorial placentation retain indications of former invasiveness of the placenta. The recent availability of comprehensive molecular phylogenies for placental mammals has provided an independent framework to determine the most parsimonious interpretation of the evolution of placenta types and other reproductive features. It has consistently emerged that epitheliochorial placentation is best explained as a derived condition, although opinions differ as to whether the ancestral condition for placental mammals (and hence for primates) was endotheliochorial or haemochorial. It is argued that on balance the most likely ancestral condition is endotheliochorial. Comparative evidence across placentals clearly indicates that epitheliochorial placentation is not less efficient than more invasive forms of placentation, at least with respect to growth in overall fetal body mass. The ratio of neonate mass to gestation period (a simple indicator of average daily maternal investment in fetal growth) shows no difference according to placenta type. Differential evolution of placentation is hence presumably linked to immunological factors, parent/offspring conflict and/or genomic imprinting.     

Survival and size are differentially regulated by placental and fetal PKBalpha/AKT1 in mice

The importance of placental circulation is exemplified by the correlation of placental size and blood flow with fetal weight and survival during normal and compromised human pregnancies in such conditions as preeclampsia and intrauterine growth restriction (IUGR). Using noninvasive magnetic resonance imaging, we evaluated the role of PKBalpha/AKT1, a major mediator of angiogenesis, on placental vascular function. PKBalpha/AKT1 deficiency reduced maternal blood volume fraction without affecting the integrity of the fetomaternal blood barrier. In addition to angiogenesis, PKBalpha/AKT1 regulates additional processes related to survival and growth. In accordance with reports in adult mice, we demonstrated a role for PKBalpha/AKT1 in regulating chondrocyte organization in fetal long bones. Using tetraploid complementation experiments with PKBalpha/AKT1-expressing placentas, we found that although placental PKBalpha/AKT1 restored fetal survival, fetal PKBalpha/AKT1 regulated fetal size, because tetraploid complementation did not prevent intrauterine growth retardation. Histological examination of rescued fetuses showed reduced liver blood vessel and renal glomeruli capillary density in PKBalpha/Akt1 null fetuses, both of which were restored by tetraploid complementation. However, bone development was still impaired in tetraploid-rescued PKBalpha/Akt1 null fetuses. Although PKBalpha/AKT1-expressing placentas restored chondrocyte cell number in the hypertrophic layer of humeri, fetal PKBalpha/AKT1 was found to be necessary for chondrocyte columnar organization. Remarkably, a dose-dependent phenotype was exhibited for PKBalpha/AKT1 when examining PKBalpha/Akt1 heterozygous fetuses as well as those complemented by tetraploid placentas. The differential role of PKBalpha/AKT1 on mouse fetal survival and growth may shed light on its roles in human IUGR.     

Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth

Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth.     

Fetal and placental size and risk of hypertension in adult life.

OBJECTIVE--To study the effect of intrauterine growth and maternal physique on blood pressure in adult life. DESIGN--A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail. SETTING--Preston, Lancashire. SUBJECTS--449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire. MAIN OUTCOME MEASURES--Placental weight, birth weight, and blood pressure at age 46 to 54 years. RESULTS--In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences. CONCLUSIONS--These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.     

Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus

Fetal and placental growth rate in sheep has been manipulated by removal of endometrial caruncles prior to conception. This produced two groups of fetuses, one in which prenatal growth rate was similar to normal and a second group in which the fetuses were about half of the normal size. The mortality in the latter group was high, particularly after catheterisation, and there was evidence of early intra-uterine death and fetal reabsorption. Prior to 125 days the relationship between fetal and placental size was poor, but after 126 days a close correlation between the two was apparent. The small fetuses had comparably small placentas and in all cases there was a close relationship between fetal and placental weight. The experimental growth retardation was associated with hypoglycaemia, hypoxia and hypoinsulinaemia. Plasma T3, T4 and particularly prolactin were very low in the small fetuses whilst levels of cortisol and alanine were high. In contrast to the controls these fetuses showed little evidence of net glucose, alanine or lactate consumption. Infusion of 50% glucose into the pregnant ewe, sufficient to elevate maternal plasma glucose concentrations 2 to 3 fold, caused a comparable increase in the plasma concentrations of normal fetuses but only a 50% rise in the concentration in small fetuses. In contrast administration of 50% O2 to the ewes sufficient to cause a 2 to 3-fold increase in maternal PO2 caused only a small increase of arterial PO2 of normal fetuses but doubled that to normal levels in small fetuses. The results are discussed in relation to the effect of reduced placental size causing a fall in placental and transport and transport capacity and significance of this to the associated fetal growth retardation.     

Changes in placental dipeptidyl peptidase IV in preeclampsia with intrauterine growth restriction.

The purpose of this study was to examine alterations in placental expression of dipeptidyl peptidase IV (DPPIV). The localization of DPPIV was compared in control and preeclamptic placentas. Enzyme activity, mRNA, and protein expression were also measured. In term placentas, DPPIV was expressed preferentially in the fetal vascular endothelial cells within stem villi and only weakly in the villous stromal cells. DPPIV activity in control placentas showed no remarkable changes throughout gestation. Levels of activity in samples from normotensive control cases and women having preeclampsia with or without intrauterine growth restriction were 11.8 +/- 2.1, 13.4 +/- 1.1, and 15.3 +/- 0.62 pmol pNA/min/mg protein, respectively. The preeclamptic placentas with intrauterine growth restriction thus showed significantly higher levels of activity than the controls (p < 0.05). We propose that placental DPPIV influences fetal metabolism via the degradation of fetoplacental circulating bioactive peptides, including incretins, resulting in the regulation of fetal growth.     

Placental and fetal growth and development in late rat gestation is dependent on adrenomedullin

Adrenomedullin is a potent, endogenous vasodilator peptide synthesized and secreted by diverse locations such as adrenal glands, lungs, kidneys, vascular smooth muscle, and endothelium. Homozygous deletion of the adrenomedullin gene is embryonic lethal. We hypothesized that adrenomedullin has an important role in placental and fetal growth and development in rat pregnancy. The current study evaluated maternal systolic blood pressure, litter size, placental and pup weight, pup mortality, and placental pathology in pregnant rats following continuous in utero exposure to an adrenomedullin antagonist. Osmotic minipumps were inserted on Gestational Day 14 to continuously deliver either adrenomedullin, adrenomedullin antagonist, or vehicle control. Systolic blood pressure was recorded daily. Pregnant rats were killed on Gestational Day 15-18, 20, and/or 22 to evaluate placental development and fetal growth. The placentas were graded for the presence of necrosis in the decidua and fetal labyrinth as well as fetal vessel development in the labyrinth. A trend toward increased systolic blood pressure was noted between Gestational Days 17 and 20 in mothers treated with adrenomedullin antagonist, but the difference was not statistically significant. Antagonism of adrenomedullin function during rat pregnancy caused fetal growth restriction, decreased placental size, gross necrosis of placental margins and amniotic membranes, histologically deficient fetal vessel development in the labyrinth, and fetal edema. Adrenomedullin contributes to angiogenesis, functions as a growth factor, and helps regulate vascular tone during rat gestation.     

Placental isoprostane is significantly increased in preeclampsia.

We determined placental tissue levels, production rates, and secretion rates of isoprostanes for placentas obtained from women with normal pregnancies and women with preeclampsia, a hypertensive disorder of pregnancy. Isoprostanes are markers of oxidative stress that exert biological actions such as vasoconstriction. Placental tissue was rinsed and immediately frozen in liquid nitrogen to determine tissue levels of total and free isoprostane. Placental tissue pieces were also incubated in serum-free DMEM for 48 h at 37 degrees C in 95% air/5% CO(2) to determine production rates. Isolated placental cotyledons were perfused for the determination of secretion rates. All samples were analyzed by EIA for isoprostane using an antibody specific for 8-Iso-PGF(2) (15-F(2t)-IsoP). In addition, medium samples were analyzed for malondialdehyde (MDA), a breakdown product of lipid peroxidation. We found that tissue levels of free isoprostane and total isoprostane (free plus esterified forms) were significantly higher for preeclamptic placentas than for normal placentas. Concentrations of isoprostane and MDA in the medium increased progressively during 48 h of incubation of placental explants. At 48 h of incubation, the mean concentrations of both isoprostane and MDA were significantly higher for the placentas from preeclamptic women than for the placentas from normal pregnant women. Concentrations of MDA were highly correlated with those of isoprostane. Induction of oxidative stress with xanthine plus xanthine oxidase increased placental production of isoprostane by normal tissue to a level similar to that of preeclamptic tissue. Placental secretion of isoprostane was eightfold greater toward the maternal side of the placenta than toward the fetal side, and was increased sixfold on the maternal side and twofold on the fetal side by inducing oxidative stress with t-butyl hydroperoxide. This study presents new information that isoprostanes are formed and secreted by the human placenta and provides convincing evidence that oxidative stress and lipid peroxidation are abnormally increased in placentas of preeclamptic women.     

The intrauterine origins of Hodgkin's lymphoma

Background: Both small and large body size at birth are now known to predict a range of chronic disorders in adult life, including certain cancers. These associations are thought to reflect “fetal programming.” This may lead to impairment of a small number of key systems including the immune system. Hodgkin's lymphoma is a disease of the immune system. We have therefore examined the association between Hodgkin's lymphoma and early development. Our hypothesis was that the disease would be associated with markers of poor fetal growth, specifically small body size or small placental size at birth. Methods: Using the Finnish Cancer Registry we identified patients with Hodgkin's disease in a cohort of 20,431 people born in Helsinki during 1924–44. Each person has a detailed birth record. Results: There were 12 patients with Hodgkin's disease, giving an incidence comparable to international rates. The disease was associated with prolonged gestation. For every additional week of gestation the hazard ratio was 1.37 (95% CI 1.00–1.87; p = 0.05). The disease was also associated with a short placental surface. After allowing for gestation, for each centimetre increase in surface length, the hazard ratio was 0.70 (0.53–0.92; p = 0.01). The disease was not associated with birth weight or length or maternal body size. Conclusions: We have shown that Hodgkin's lymphoma is associated with prolonged gestation and a short length of the placental surface. We speculate that Hodgkin's lymphoma is initiated by two events in fetal life. One, which is an immune event, is associated with prolonged gestation, while the other is associated with growth faltering.     

Fetal and placental weight relationships in the rat at days 13 and 17 of gestation

Mean fetal and placental weights were, respectively, 0.018 and 0.051 g on Day 13 and 0.376 and 0.250 g on Day 17. Fetal and placental weights within litters were weakly correlated on Day 13 (r = 0.322) but not on Day 17. Litter size was negatively correlated with placental weight on Day 17 (r = -0.485) but not with fetal weight. Male fetuses were heavier than female fetuses on Day 17 but their placentas were not significantly different. Fetuses and placentas were lighter at the ovarian end of the uterine horn on both days examined, revealing an early influence of local environmental factors on their growth.     

Growth and in-vitro metabolism of placental tissues of cows from day 100 to day 250 of gestation.

Weight of placental tissues of cows increased exponentially from Day 100 to Day 250 of gestation, but at much slower relative and absolute rates than fetal weight. In addition, growth rate of fetal placental tissues was less than that of maternal placental tissues. Concentrations of DNA, RNA and protein, however, increased in fetal placental but not in maternal placental tissues. Fetal placental tissues therefore exhibited hyperplasia, which probably contributes to increased functional capacity of the placenta during late gestation. The rate of O2 uptake in vitro was greatest for maternal placental tissues, suggesting that the maternal portion of the placenta accounts for most of the large rate of placental O2 utilization in vivo. Compared with other placental tissues, rate of secretion of macromolecules by intercaruncular endometrium was high, but decreased from Day 100 to 250, suggesting that uterine glandular secretory activity may decrease as gestation advances. Rate of secretion of macromolecules also was high for intercotyledonary tissues and increased with day of gestation, suggesting a role for secretory products of chorioallantois in gravid uterine function.     

Influence of cloning by chromatin transfer on placental gene expression at Day 45 of pregnancy in cattle

Poor success rates in somatic cell cloning are often attributed to abnormal early embryonic development as well as late abnormal fetal growth and placental development. Although promising results have been reported following chromatin transfer (CT), a novel cloning method that includes the remodeling of the donor nuclei in vitro prior to their transfer into enucleated oocytes, animals cloned by CT show placental abnormalities similar to those observed following conventional nuclear transfer. We hypothesized that the placental gene expression pattern from cloned fetuses was ontologically related to the frequently observed placental phenotype. The aim of the present study was to compare global gene expression by microarray analysis of Day 44–47 cattle placentas derived from CT cloned fetuses with those derived from in vitro fertilization (i.e. control), and confirm the altered mRNA and protein expression of selected molecules by qRT-PCR and immunohistochemistry, respectively. The differentially expressed genes identified in the present study are known to be involved in a range of activities associated with cell adhesion, cell cycle control, intracellular transport and proteolysis. Specifically, an imprinted gene, involved with cell proliferation and placentomegaly in humans (CDKN1C) and a peptidase that serves as a marker for non-invasive trophoblast cells in human placentas (DPP4), had mRNA and protein altered in CT placentas. It was concluded that the altered pattern of gene expression observed in CT samples may contribute to the abnormal placental development phenotypes commonly identified in cloned offspring, and that expression of imprinted as well as trophoblast invasiveness-related genes is altered in cattle cloned by CT.     

Antenatal administration of celecoxib,a selective cyclooxygenase (COX)-2 inhibitor,appears to improve placental perfusion in the pregnant rabbit

To investigate the effects of celecoxib on fetal growth, and placental prostanoid and nitric oxide (NO) production in fetal rabbits, pregnant rabbits received celecoxib (30 mg/kg per day) from 13 to 20 days (Cel-A), from 13 to 28 days (Cel-B), or vehicle from 13 to 28 days gestation. Fetal body and organ weights, and measurements of linear growth were recorded. The placentas were weighed and analyzed for prostaglandins (PGs), NO oxidation products (NOx), and total cellular protein levels. Placental prostaglandin E2 (PGE2) and NOx levels increased (P < or = 0.05), while thromboxane B2 levels were suppressed (P < or = 0.01) in Cel-B group. Tail length and brain weight were greater, while lung weights were lower in the Cel-B group (P < or = 0.05). Maternal administration of celecoxib appears to preferentially increase placental vasodilators and decrease placental TxA2, suggesting that the drug may increase uteroplacental perfusion without adverse fetal outcome.     

Prenatal exposure to dexamethasone in the mouse induces sex‐specific differences in placental gene expression

Prenatal stress during pregnancy leads to sex‐specific effects on fetal development and disease susceptibility over the life span; however, the origin of sex differences has not been identified. The placenta not only plays a key role in fetal growth and development throughout pregnancy, but also affects the fetal programming underlying subsequent adult health and accounts. Therefore, sex‐specific adaptation of the placenta may be central to the sex differences in fetal growth and survival. Here, we analyzed the effects of prenatal dexamethasone (Dex) on sex‐specific changes in placental gene expression using RNA‐Seq. Placental tissues from males and females were separated into two developmentally distinct fetal and maternal parts at E11.5 stage. The majority of genes in female placentas were downregulated by prenatal Dex, whereas those were mostly maintained or rather upregulated in male placentas. RNA‐Seq results were validated using independent biological replicates from the same stage and placental tissue samples from E18.5 by realtime PCR assays. Activation of various inflammatory response‐related genes, chemokines and their receptors, particularly in male placentas, strongly implies that prenatal Dex exposure causes sex‐specific physiological responses that can lead to inflammatory diseases involving vascular pathology.