Placentas Of Male Fetuses Research Articles

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Obesity downregulates lipid metabolism genes in first trimester placenta

Placentas of obese women have low mitochondrial β-oxidation of fatty acids (FA) and accumulate lipids in late pregnancy. This creates a lipotoxic environment, impairing placental efficiency. We hypothesized that placental FA metabolism is impaired in women with obesity from early pregnancy. We assessed expression of key regulators of FA metabolism in first trimester placentas of lean and obese women. Maternal fasting triglyceride and insulin levels were measured in plasma collected at the time of procedure. Expression of genes associated with FA oxidation (FAO; ACOX1, CPT2, AMPKα), FA uptake (LPL, LIPG, MFSD2A), FA synthesis (ACACA) and storage (PLIN2) were significantly reduced in placentas of obese compared to lean women. This effect was exacerbated in placentas of male fetuses. Placental ACOX1 protein was higher in women with obesity and correlated with maternal circulating triglycerides. The PPARα pathway was enriched for placental genes impacted by obesity, and PPARα antagonism significantly reduced 3H-palmitate oxidation in 1st trimester placental explants. These results demonstrate that obesity and hyperlipidemia impact placental FA metabolism as early as 7 weeks of pregnancy.

Paternal diabetes programs sex-dependent placental alterations and fetal overgrowth.

The aim of this study was to evaluate the paternal programming of sex-dependent alterations in fetoplacental growth and placental lipid metabolism regulated by peroxisome proliferator-activated receptor (PPAR) target genes in F1 diabetic males born from F0 pregestational diabetic rats. F1 control and diabetic male rats were mated with control female rats. On day 21 of gestation, F2 male and female fetoplacental growth, placental lipid levels, and protein and mRNA levels of genes involved in lipid metabolism and transport were evaluated. Fetal but not placental weight was increased in the diabetic group. Triglyceride, cholesterol and free fatty acid levels were increased in placentas of male fetuses from the diabetic group. The mRNA levels of Pparα and Pparγ coactivator 1α (Pgc-1α) were increased only in placentas of male fetuses from the diabetic group. Protein levels of PPARα and PGC-1α were decreased only in placentas of male fetuses from the diabetic group. No differences were found in Pparγ mRNA and protein levels in placentas from the diabetic group. The mRNA levels of genes involved in lipid synthesis showed no differences between groups, whereas the mRNA levels of genes involved in lipid oxidation and transport were increased only in placentas of male fetuses from the diabetic group. In conclusion, paternal diabetes programs fetal overgrowth and sex-dependent effects on the regulation of lipid metabolism in the placenta, where only placentas of male fetuses show an increase in lipid accumulation and mRNA expression of enzymes involved in lipid oxidation and transport pathways.

Sex-specific difference in placental inflammatory transcriptional biomarkers of maternal phthalate exposure: a prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to birth outcomes in a sex-specific manner. These outcomes may be mediated by placental inflammation, which is the proposed biological mechanism. This is the first study to address the relationship between phthalate exposure and gene expression in placental inflammation in a sex-specific manner. We performed quantitative PCR to measure placental inflammatory mRNAs (CRP, TNF-α, IL-1β, IL-6, IL-10, MCP-1, IL-8, CD68, and CD206) in 2469 placentae that were sampled at birth. We estimated the associations between mRNA and urinary phthalate monoesters using multiple linear regression models. Mono-n-butyl phthalate (MBP) was correlated with higher IL-1β, IL-6, and CRP expression in placentae of male fetuses and with higher IL-6, CRP, MCP-1, IL-8, IL-10, and CD68 expression in placentae of female fetuses. Mono benzyl phthalate (MBzP) increased the expression of TNF-α, MCP-1, and CD68 only in placentae of male fetuses. Mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with CRP, MCP-1, and CD68 in placentae of female fetuses. Maternal phthalate exposure was associated with inflammatory variations in placental tissues. The associations were stronger in placentae of male than of female fetuses. Compared with the other metabolites, MBP plays a strong role in these associations. The placenta is worth being further investigated as a potential mediator of maternal exposure-induced disease risk in children.

Mid- to late term hypoxia in the mouse alters placental morphology, glucocorticoid regulatory pathways and nutrient transporters in a sex-specific manner.

Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid- to late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults.

Maternal Corticosterone Exposure in the Mouse Has Sex-Specific Effects on Placental Growth and mRNA Expression

Maternal exposure to increased synthetic glucocorticoids (GC) during pregnancy is known to disturb fetal development and increase the risk of long-term disease. Maternal exposure to elevated levels of natural GC is likely to be common yet is relatively understudied. The placenta plays an important role in regulating fetal exposure to maternal GC but is itself vulnerable to maternal insults. This study uses a mouse model of maternal corticosterone (Cort) exposure to investigate its effects on the developing placenta. Mice were treated with Cort (33 μg/kg·h) for 60 h starting at embryonic d 12.5 (E12.5) before collection of placentas at E14.5 and E17.5. Although Cort exposure did not affect fetal size, placentas of male fetuses were larger at E17.5 in association with changes in placental Igf2. This increase in size was associated with an increase in placental thickness and an increase in placental junctional zone volume. Placentas from female fetuses were of normal size and had no changes in growth factor mRNA levels. The expression of the protective enzyme 11β-hydroxysteroid dehydrogenase type 2 was increased at E14.5 but was decreased in males at E17.5. In contrast, the expression of Nr3c1 (which encodes the GC receptor) was increased during the Cort exposure and remained elevated at E17.5 in the placentas of male fetuses. Our study has shown that maternal Cort exposure infers a sex-specific alteration to normal placental growth and growth factor expression, thus further adding to our understanding of the mechanisms of male dominance of programmed disease.

The Placental Response to Excess Maternal Glucocorticoid Exposure Differs Between the Male and Female Conceptus in Spiny Mice1

The placenta is the intermediary between the mother and fetus, and its primary role is to provide for the appropriate growth of the fetus. A suboptimal in utero environment has been shown to differentially affect the health of offspring, depending on their sex. Here we show that excess maternal glucocorticoids administered in midgestation (Day 20, 0.5 gestation in the spiny mouse) for 60 h, have persisting effects on the placenta that differ by fetal sex, placental region, and time after glucocorticoid exposure. Dexamethasone (DEX) exposure altered placental structure and mRNA expression from male and female fetuses both immediately (Day 23) and 2 wk posttreatment (Day 37). The immediate consequences (Day 23) of DEX were similar between males and females, with reductions in the expression of IGF1, IGF1R, and SLC2A1 in the placenta. However, by Day 37, the transcriptional and structural response of the placenta was dependent on the sex of the fetus, with placentas of male fetuses having an increase in GCM1 expression, a decrease in SLC2A1 expression, and an increase in the amount of maternal blood sinusoids in the DEX-exposed placenta. Female placentas, on the other hand, showed increased SLC2A1 and MAP2K1 expression and a decrease in the amount of maternal blood sinusoids in response to DEX exposure. We have shown that the effect of a brief glucocorticoid exposure at midgestation has persisting effects on the placenta, and this is likely to have ongoing and dynamic effects on fetal development that differ for a male and female fetus.

Placental Cytokine Expression Covaries with Maternal Asthma Severity and Fetal Sex

In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.

Expression of Glucocorticoid Receptor Messenger Ribonucleic Acid Transcripts in the Human Placenta at Term

Differential promoter use and alternative splicing generate a variety of glucocorticoid receptor (GR) mRNA transcripts, potentially altering the cortisol responsiveness of gestational tissues during pregnancy and labor. We examined GR mRNA transcript expression in term placentae before and after labor, in association with fetal sex and after glucocorticoid treatment. RNA from 34 placentae and from eight placental explants incubated with glucocorticoids were analyzed for the GR mRNA variants GR-alpha, GR-beta, GR-P, and GR-gamma and the untranslated exon one variants 1A1, 1A2, 1A3, 1B, and 1C by quantitative RT-PCR. mRNA expression was assessed. All GR mRNA variants examined were detected in the human placenta, with GR-alpha and GR-1C mRNA having the highest expression of GR splice variants and exon 1 variants, respectively. GR-P mRNA abundance decreased with spontaneous labor (P < 0.01). GR-1A3 mRNA abundance changed with fetal sex, with a higher level in placentae of male fetuses (P < 0.05). GR-1C was the preferential promoter for GR-alpha, GR-gamma, and GR-P mRNA. GR-beta mRNA was preferentially associated with GR-1A1. GR-P mRNA transcription switched to the GR-1A1 promoter after labor and to the GR-1A3 promoter in placentae from male fetuses. Glucocorticoid treatment significantly reduced transcription from promoters GR-1B and -1C and decreased GR-alpha and GR-P mRNA abundance. The human placenta expresses a variety of GR mRNA transcripts. GR-alpha mRNA transcribed from the 1C promoter generates the majority of placental GR. However, alterations in promoter use and alternative splicing may modulate responses to cortisol during stressful events.

Genetic origin and proportion of basal plate surface cells in normal and abnormal pregnancies

The basal plate of the placenta is the floor of the intervillous space. The cellular constituents of the basal plate surface that are in direct contact with maternal blood include trophoblasts (TB; of fetal origin) and endothelial cells (EC) whose origin (fetal or maternal) is unknown. This study was conducted to 1) determine the origin of these EC; and 2) to assess the relative proportion of TB and EC covering the intervillous surface of the basal plate in placentas from normal and preeclamptic pregnancies. Placentas from patients with normal term gestations (n = 9) and preeclampsia (n = 10) were included. Five sections of the basal plate were obtained from the central, paracentral and peripheral regions of each placenta. Double immunohistochemistry (vimentin: EC and cytokeratin 7: TB) and image analysis were performed. Seven placentas of male fetuses were used to evaluate the origin of the EC. Genomic DNA isolated from laser microdissected EC was subjected to PCR for sex typing. Data were analyzed using non-parametric statistics. 1) The median proportion of TB and EC covering the basal plate surface in normal placentas was 8% (range 6.5-17.6%) and 13.6% (range: 4.4-24.6%), respectively; 2) the median TB/EC ratio was 0.8 (range: 0.3-4); 3) in preeclampsia, the basal plate surface showed a higher proportion of TB than those from normal pregnancies (median: 17.6%, range: 5.9-29.2%, p = 0.04); 4) a trend towards a lower proportion of EC in preeclampsia was observed; and 5) EC covering the basal plate were of maternal origin. 1) For the first time, EC lining the intervillous space surface of the basal plate have been identified to be of maternal origin; and 2) preeclampsia is associated with an excess of TB covering the surface of the basal plate.

Sex differences in plasma corticosterone in mouse fetuses are mediated by differential placental transport from the mother and eliminated by maternal adrenalectomy or stress

The effect of changes in maternal corticosterone concentrations, induced by maternal stress, maternal adrenalectomy or both, on concentration of corticosterone in serum and in adrenals of mouse (Mus domesticus) fetuses was examined. Higher baseline serum corticosterone concentrations were found in female fetuses than in male fetuses; however, there was no sex difference in the content of corticosterone in adrenals collected from these fetuses. Sex differences were observed in the fetal response to changes in maternal concentrations of serum corticosterone resulting from stress (bright light and heat) or adrenalectomy, and both factors eliminated the sex difference in corticosterone in fetal serum. When females were injected i.v. with [3H]corticosterone on day 17 of pregnancy, significantly more 3H was recovered from the serum of female than of male fetuses 15 min after the injection, while more 3H was recovered from placentae of male fetuses. This finding suggests that the difference in serum corticosterone in male and female mouse fetuses is due to greater transport of corticosterone from maternal blood across the placenta of female than of male fetuses.