Association among placental 11β‐HSD2, PPAR‐γ, and NF‐κB p65 in small‐for‐gestational‐age infants: A nested case‐control study

Fu, Lin; Bo, Qingli; Gan, Yu; Chen, Yuan-Hua; Zhao, Hui; Tao, Fangbiao; D, Xu

doi:10.1111/aji.13231

Cited by 6 publications

(7 citation statements)

References 37 publications

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“…This implies that placental infection-induced inflammation is associated with lower placental weight. As mentioned above, the increase in pro-inflammatory cytokines, and activation of the components of the inflammasomes cascade, is consistently reported in pregnancies associated with placental inflammation [17,37,[47][48][49][50][51][52][53][54][55][56][57][58][59]. This study demonstrates that the reduction of placental weight and birth weight in FGR may be associated with sterile inflammation, specifically when there are no signs of infection associated with the FGR placentae included in this study.…”

Section: Discussionsupporting

confidence: 71%

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

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Section: Discussionsupporting

confidence: 71%

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

Alfian

Chakraborty

Yong

et al. 2022

Cells

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“…Placental 11β‐HSD2 inactivates maternal glucocorticoids, and its expression is regulated by PPARγ. In a study of SGA and AGA newborns (Fu et al, 2020), placental 11β‐HSD2 was lower in SGA than in AGA placentas. Inflammatory cytokines were higher in placentas from SGA infants.…”

Section: Resultsmentioning

confidence: 95%

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

Rogers

Heintz

Thompson

et al. 2023

Birth Defects Research

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Background Some per‐ and poly‐fluoroalkyl substances (PFAS) cause neonatal mortality and lower birth weight in rodents. We constructed an Adverse Outcome Pathway (AOP) network for neonatal mortality and lower birth weight in rodents, comprising three putative AOPs. We then assessed strengths of the evidence for the AOPs and applicability to PFAS. Finally, we considered the relevance of this AOP network to human health. Methods Literature searches targeted PFAS, peroxisome proliferator‐activated receptor (PPAR) agonists, other nuclear receptors, relevant tissues, and developmental targets. We used reviews of established biology and described results of studies with prenatal PFAS exposure that assessed birth weight and neonatal survival. Molecular initiating events (MIEs) and key events (KEs) were proposed and strengths of KE relationships (KERs), applicability to PFAS, and human relevance were assessed. Results Neonatal mortality has been observed in rodents following gestational exposure to most longer chain PFAS studied, often coincident with lower birth weight. In AOP 1, PPARα activation and PPARγ activation or downregulation are MIEs; placental insufficiency, fetal nutrient restriction, neonatal hepatic glycogen deficit, and hypoglycemia are KEs leading to neonatal mortality and lower birth weight. In AOP 2, constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activation upregulates Phase II metabolism, lowering maternal circulating thyroid hormones. In AOP 3, disrupted pulmonary surfactant function and PPARγ downregulation cause neonatal airway collapse and mortality from respiratory failure. Conclusions It is likely that different components of this AOP network will apply to different PFAS, largely determined by which nuclear receptors they activate. The MIEs and KEs in this AOP network can occur in humans, but differences in PPAR structure and function, and the timeline of liver and lung development, suggest that humans may be less susceptible to this AOP network. This putative AOP network elucidates knowledge gaps and research needed to better understand the developmental toxicity of PFAS.

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“…[8][9][10] Inflammation has been proposed to be a responsible factor. 11 Less cortisol is thus metabolized to cortisone, which does not activate the cortisol receptor. Increased cortisol release in response to stress decreases choline concentrations, presumably by causing the liver and other organs to sequester choline as phosphatidylethanolamine.…”

Section: Discussionmentioning

confidence: 99%

“…6 Several risk factors for SGA have been identified in observational studies including increased cortisol levels, increased inflammation often measured as increased maternal C-reactive protein (CRP), and female fetal sex. [7][8][9][10][11][12][13][14][15][16] Maternal nutrition has not generally been considered as a risk factor or as a preventative intervention. However, recent studies have shown effects of choline and its metabolite betaine on birth weight.…”

mentioning

confidence: 99%

Maternal Plasma Choline during Gestation and Small for Gestational Age Infants

et al. 2022

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Objective Small for gestational age (SGA) infants are at increased risk for neonatal morbidity and developmental problems in childhood. No current interventions during human pregnancy address this problem. This study investigated the possible relationship between maternal choline concentration during pregnancy and SGA infants. Study Design Maternal plasma choline concentrations were sampled at 16 and 28 weeks' gestation from women in a public prenatal clinic. Additional factors assessed were maternal age, body mass index, infection, C-reactive protein, hair cortisol, and compliance with prenatal vitamins and folate. Infants below the 10th percentile for gestational age were classified as SGA. Binary logistic regression was used to identify significant associated factors in pregnancies resulting in SGA infants compared with pregnancies resulting in non-SGA infants. Results Thirteen (8%) of 159 women had SGA infants. Maternal plasma choline concentrations were low for pregnant participants whose infants were SGA, with the 28-week concentration significantly lower compared with other participants. Plasma choline concentrations ≥7 μM at 28 weeks, consistent with a minimally adequate dietary intake of choline-containing foods, were achieved by only 2 (15%) of mothers with SGA infants, compared with 51% of mothers whose infants were not SGA. Choline concentrations <7 μM at 28 weeks' gestation were associated with an odds ratio for SGA of 16.6 (95% confidence interval: 1.5–189.2, p = 0.023). Other significant factors were female sex and maternal C-reactive protein plasma concentration during gestation. Conclusion This observational study suggests that higher maternal choline levels may influence the risk for SGA. Maternal plasma choline concentrations are not routinely available in clinical laboratories. However, plasma choline levels can be increased by the mothers' intake of choline or phosphatidylcholine supplements. No nutritional intervention is currently recommended to prevent SGA, but the evidence from this study suggests that further consideration of the role of maternal choline may be warranted. Key Points

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Association among placental 11β‐HSD2, PPAR‐γ, and NF‐κB p65 in small‐for‐gestational‐age infants: A nested case‐control study

Cited by 6 publications

References 37 publications

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

Maternal Plasma Choline during Gestation and Small for Gestational Age Infants

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