The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma

Saif, Zarqa; Hodyl, Nicolette A.; Hobbs, E.; Tuck, Astrud R.; Butler, Miriam; Osei-Kumah, A.; Clifton, Vicki L.

doi:10.1016/j.placenta.2014.01.012

Cited by 85 publications

(87 citation statements)

References 25 publications

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“…For example, in human AECs, 48 h of hypoxia downregulates the GR␣ subtype (39). In the present study, we found no change in mRNA expression of GR, but we did find a decrease in PR fetuses in the 94-and 91-kDa forms of GR, which correspond to known GR isoforms, GR␣ and GR␤, respectively (76). Interestingly, we found a 3.5-5.0-fold greater expression of GR␤ compared with GR␣ in the lung.…”

Section: Resultscontrasting

confidence: 64%

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Orgeig

McGillick

Botting

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130-135 (n = 19) and 139-145 (n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain (PHD)2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α (HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.

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Section: Resultscontrasting

confidence: 64%

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Orgeig

McGillick

Botting

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Previous studies have reported a higher incidence of SGA females with the combination of maternal smoking and asthma [30]. Several mechanistic studies have shown that there are sex-specific differences in the fetal response to maternal asthma that may be conferred by a difference in glucocorticoid sensitivity of the male and female placenta [31, 32]. These findings suggest males and females respond differently to the presence of maternal asthma and institute different strategies in relation to growth, which may also contribute to difference in perinatal outcomes.…”

Section: Discussionmentioning

confidence: 99%

Patterns, predictors and outcomes of asthma control and exacerbations during pregnancy: a prospective cohort study

et al. 2016

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There exists a paucity of data for socially disadvantaged populations describing patterns and predictors of asthma control status and exacerbations during pregnancy, and their relationship to adverse perinatal outcomes.Asthmatic women (n=189) were followed prospectively during pregnancy, with visits at 12, 20, 28 and 36 weeks gestation. Data on loss of control, recurrent uncontrolled asthma and moderate/severe exacerbations were collected at each visit and their relationship to perinatal outcomes examined following stratification for fetal sex.50% of asthmatic women experienced a loss of control or moderate/severe exacerbation during pregnancy, with 22% of women experiencing a moderate/severe exacerbation. Factors associated with an increased risk of women experiencing recurrent uncontrolled asthma during pregnancy included smoking (relative risk 2.92, 95% CI 1.53–5.58), inhaled corticosteroid use at the beginning of pregnancy (relative risk 2.40, 95% CI 1.25–4.60) and increasing maternal age (relative risk 1.06, 95% CI 1.01–1.11). No factors were associated with moderate/severe exacerbations. Asthma control rather than exacerbations during pregnancy appeared to be most strongly correlated with perinatal outcomes. Following stratification by fetal sex, the presence of recurrent uncontrolled asthma was associated with an increased risk of being small for gestational age in women pregnant with females (33.3% versus 9.5%; p=0.018). In contrast, there was a nonsignificant increased risk of preterm birth in women with recurrent uncontrolled asthma that were pregnant with males (25.0% versus 11.8%; p=0.201)These results suggest that the key to improving perinatal outcomes lies in improving asthma control as early as possible in pregnancy and monitoring throughout pregnancy, rather than focusing on preventing exacerbations alone.

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“…The specific forms vary based on fetal sex and size, placental stage (preterm vs term), and maternal asthmatic state (70,71). In preterm placentae, GRa D2 expression was higher in males than females.…”

Section: Stress Hormonesmentioning

confidence: 99%

Sex-Specific Placental Responses in Fetal Development

2015

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The placenta is an ephemeral but critical organ for the survival of all eutherian mammals and marsupials. It is the primary messenger system between the mother and fetus, where communicational signals, nutrients, waste, gases, and extrinsic factors are exchanged. Although the placenta may buffer the fetus from various environmental insults, placental dysfunction might also contribute to detrimental developmental origins of adult health and disease effects. The placenta of one sex over the other might possess greater ability to respond and buffer against environmental insults. Given the potential role of the placenta in effecting the lifetime health of the offspring, it is not surprising that there has been a resurging interest in this organ, including the Human Placental Project launched by the National Institutes of Child Health and Human Development. In this review, we will compare embryological development of the laboratory mouse and human chorioallantoic placentae. Next, evidence that various species, including humans, exhibit normal sex-dependent structural and functional placental differences will be examined followed by how in utero environmental changes (nutritional state, stress, and exposure to environmental chemicals) might interact with fetal sex to affect this organ. Recent data also suggest that paternal state impacts placental function in a sex-dependent manner. The research to date linking placental maladaptive responses and later developmental origins of adult health and disease effects will be explored. Finally, we will focus on how sex chromosomes and epimutations may contribute to sex-dependent differences in placental function, the unanswered questions, and future directions that warrant further consideration.

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The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma

Cited by 85 publications

References 25 publications

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Patterns, predictors and outcomes of asthma control and exacerbations during pregnancy: a prospective cohort study

Sex-Specific Placental Responses in Fetal Development

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