Pub Date : 2026-01-14DOI: 10.1016/j.placenta.2026.01.008
Louis Samson , Stephanie Worrell , Cláudia M. Salgado , Emilio Medina-Ceballos , Daisy Wu , Lauren B. Skvarca , Natalie I. Larsen , Nicole N. Balmer , Ona Marie Faye-Petersen , Robert Bendon , Stewart Cramer , Miguel Reyes-Múgica
Background
Systematic evaluation of the umbilical cord is an integral part of placental examination. Among the important parameters of this exam is the assessment of visible lesions such as knots and discoloration. The latter can be due to funisitis (yellow-white), meconium staining (green), vascular congestion (red-blue), or maternal hyperbilirubinemia (yellow). This case series presents fifteen examples of umbilical cord lesions characterized by foci of brown-black discoloration caused by melanin deposition.
Methods
Placental pathology reports from our institutions mentioning melanocytes or melanin in the umbilical cord were reviewed, and the slides pulled for histologic analysis by members of the pathology team. Immunohistochemical (SOX10, Melan-A, PHOX2B, and CD56) and histochemical (Fontana-Masson) staining was performed retrospectively on the umbilical cord sections.
Results
Fifteen cases of umbilical cord with grossly visible brown linear stippling or punctate discoloration were confirmed. Microscopic examination showed scattered SOX10-positive melanocytes in the amnion layer with melanin deposition and uptake by the amniocytes. Nine of the fifteen infants and none of the mothers had congenital melanocytic nevi.
Conclusion
To the best of our knowledge, this is the first description of melanocytes and melanin pigment in the umbilical cord. We propose that an aberrant migration of neural crest cells into the umbilical cord, with subsequent differentiation into melanocytes, is the most likely pathogenesis.
{"title":"Aberrant neural crest cells migration leads to melanocyte presence in the umbilical cord","authors":"Louis Samson , Stephanie Worrell , Cláudia M. Salgado , Emilio Medina-Ceballos , Daisy Wu , Lauren B. Skvarca , Natalie I. Larsen , Nicole N. Balmer , Ona Marie Faye-Petersen , Robert Bendon , Stewart Cramer , Miguel Reyes-Múgica","doi":"10.1016/j.placenta.2026.01.008","DOIUrl":"10.1016/j.placenta.2026.01.008","url":null,"abstract":"<div><h3>Background</h3><div>Systematic evaluation of the umbilical cord is an integral part of placental examination. Among the important parameters of this exam is the assessment of visible lesions such as knots and discoloration. The latter can be due to funisitis (yellow-white), meconium staining (green), vascular congestion (red-blue), or maternal hyperbilirubinemia (yellow). This case series presents fifteen examples of umbilical cord lesions characterized by foci of brown-black discoloration caused by melanin deposition.</div></div><div><h3>Methods</h3><div>Placental pathology reports from our institutions mentioning melanocytes or melanin in the umbilical cord were reviewed, and the slides pulled for histologic analysis by members of the pathology team. Immunohistochemical (SOX10, Melan-A, PHOX2B, and CD56) and histochemical (Fontana-Masson) staining was performed retrospectively on the umbilical cord sections.</div></div><div><h3>Results</h3><div>Fifteen cases of umbilical cord with grossly visible brown linear stippling or punctate discoloration were confirmed. Microscopic examination showed scattered SOX10-positive melanocytes in the amnion layer with melanin deposition and uptake by the amniocytes. Nine of the fifteen infants and none of the mothers had congenital melanocytic nevi.</div></div><div><h3>Conclusion</h3><div>To the best of our knowledge, this is the first description of melanocytes and melanin pigment in the umbilical cord. We propose that an aberrant migration of neural crest cells into the umbilical cord, with subsequent differentiation into melanocytes, is the most likely pathogenesis.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"175 ","pages":"Pages 1-6"},"PeriodicalIF":2.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.placenta.2026.01.007
Jiayi Jiang , Dianjie Li , Yixiang Zhong, Yi Zhang, Mei Zhong
{"title":"Corrigendum to “-mediated DNA hydroxymethylation of TGFB1 is related to selective intrauterine growth restriction in monochorionic twin pregnancies” [Placenta (144), December 2023, Pages 45–54]","authors":"Jiayi Jiang , Dianjie Li , Yixiang Zhong, Yi Zhang, Mei Zhong","doi":"10.1016/j.placenta.2026.01.007","DOIUrl":"10.1016/j.placenta.2026.01.007","url":null,"abstract":"","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 259-260"},"PeriodicalIF":2.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-10DOI: 10.1016/j.placenta.2026.01.006
Deniz Aydın Ceylan , Cihan Kabukçu , Yeliz Arman Karakaya
Introduction
Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by impaired placental angiogenesis and an imbalance between pro- and anti-angiogenic factors. Netrin-1, Netrin-4, and their receptor UNC5B are critical modulators of vascular development. This study investigated their immunohistochemical expression in preeclamptic and healthy placentas.
Methods
Placental tissues from 96 women with PE and 71 healthy term controls were analyzed. Immunohistochemistry was performed on tissue microarrays, and immunoreactivity scores (IRS) were calculated based on staining intensity and extent. Expression profiles were compared between groups and across disease severity and gestational age subgroups.
Results
Netrin-1 expression was significantly reduced in preeclamptic placentas compared with controls (mean IRS 3.46 ± 2.57 vs. 6.77 ± 3.17; p < 0.0001), whereas Netrin-4 and UNC5B were markedly upregulated (Netrin-4: 8.60 ± 3.22 vs. 1.92 ± 1.59; UNC5B: 4.75 ± 1.95 vs. 3.49 ± 1.30; all p < 0.0001). Netrin-1 remained consistently decreased across severity subgroups, while Netrin-4 expression was significantly higher in severe versus non-severe PE (p = 0.002). Expression levels did not differ between early- and late-onset PE. Correlation analysis showed a negative association between Netrin-1 and Netrin-4 (r = −0.425) and a positive correlation between Netrin-4 and UNC5B (r = 0.439) (both p < 0.0001).
Conclusion
PE is associated with a coordinated shift in the placental Netrin signaling axis, characterized by downregulation of the pro-angiogenic Netrin-1 and upregulation of the anti-angiogenic ligand Netrin-4 and receptor UNC5B. These findings suggest that Netrin-mediated angiogenic imbalance may play a key role in the pathogenesis of preeclampsia.
{"title":"Immunohistochemical analysis of placental Netrin-1, Netrin-4, and UNC5B in preeclampsia","authors":"Deniz Aydın Ceylan , Cihan Kabukçu , Yeliz Arman Karakaya","doi":"10.1016/j.placenta.2026.01.006","DOIUrl":"10.1016/j.placenta.2026.01.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by impaired placental angiogenesis and an imbalance between pro- and anti-angiogenic factors. Netrin-1, Netrin-4, and their receptor UNC5B are critical modulators of vascular development. This study investigated their immunohistochemical expression in preeclamptic and healthy placentas.</div></div><div><h3>Methods</h3><div>Placental tissues from 96 women with PE and 71 healthy term controls were analyzed. Immunohistochemistry was performed on tissue microarrays, and immunoreactivity scores (IRS) were calculated based on staining intensity and extent. Expression profiles were compared between groups and across disease severity and gestational age subgroups.</div></div><div><h3>Results</h3><div>Netrin-1 expression was significantly reduced in preeclamptic placentas compared with controls (mean IRS 3.46 ± 2.57 vs. 6.77 ± 3.17; <em>p</em> < 0.0001), whereas Netrin-4 and UNC5B were markedly upregulated (Netrin-4: 8.60 ± 3.22 vs. 1.92 ± 1.59; UNC5B: 4.75 ± 1.95 vs. 3.49 ± 1.30; all <em>p</em> < 0.0001). Netrin-1 remained consistently decreased across severity subgroups, while Netrin-4 expression was significantly higher in severe versus non-severe PE (<em>p</em> = 0.002). Expression levels did not differ between early- and late-onset PE. Correlation analysis showed a negative association between Netrin-1 and Netrin-4 (<em>r</em> = −0.425) and a positive correlation between Netrin-4 and UNC5B (<em>r</em> = 0.439) (both <em>p</em> < 0.0001).</div></div><div><h3>Conclusion</h3><div>PE is associated with a coordinated shift in the placental Netrin signaling axis, characterized by downregulation of the pro-angiogenic Netrin-1 and upregulation of the anti-angiogenic ligand Netrin-4 and receptor UNC5B. These findings suggest that Netrin-mediated angiogenic imbalance may play a key role in the pathogenesis of preeclampsia.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"175 ","pages":"Pages 7-15"},"PeriodicalIF":2.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The placenta is essential for fetal growth and the maintenance of pregnancy. Primary human cytotrophoblasts (CTBs) provide a physiologically relevant model of this transient organ, yet their use has been limited by the difficulty of genetic manipulation. Recombinant adeno-associated virus (AAV) vectors, widely used to modulate gene expression in other systems, offer low immunogenicity, low cytotoxicity, and high efficiency in primary cells. Here, we provide proof of concept of an AAV-mediated gene delivery approach for primary CTBs. This platform enables in-depth, cell-biological studies to elucidate molecular mechanisms of human placental biology and pathology.
{"title":"Adeno-associated viral vector-mediated gene delivery and shRNA knockdown in primary human cytotrophoblasts","authors":"Hiromichi Yamamoto , Masato Tamari , Seiji Wada , Hironori Takahashi , Hiromi Yoshida-Komiya , Hirohisa Saito , Hideaki Morita , Kenji Matsumoto , Kenichiro Motomura","doi":"10.1016/j.placenta.2026.01.005","DOIUrl":"10.1016/j.placenta.2026.01.005","url":null,"abstract":"<div><div>The placenta is essential for fetal growth and the maintenance of pregnancy. Primary human cytotrophoblasts (CTBs) provide a physiologically relevant model of this transient organ, yet their use has been limited by the difficulty of genetic manipulation. Recombinant adeno-associated virus (AAV) vectors, widely used to modulate gene expression in other systems, offer low immunogenicity, low cytotoxicity, and high efficiency in primary cells. Here, we provide proof of concept of an AAV-mediated gene delivery approach for primary CTBs. This platform enables in-depth, cell-biological studies to elucidate molecular mechanisms of human placental biology and pathology.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 254-258"},"PeriodicalIF":2.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To investigate maternal serum levels of soluble suppression of tumorigenicity-2 (sST2) in pregnancies complicated by fetal growth restriction (FGR), and to evaluate its diagnostic utility and association with adverse neonatal outcomes.
Methods
This prospective observational study comprised 88 singleton pregnancies, including 44 FGR cases and 44 healthy controls matched for gestational age. FGR was classified as early or late onset using Delphi consensus criteria. Maternal serum sST2 levels were measured between 28 and 37 weeks of gestation by ELISA. Correlation analyzes and ROC curve analyzes were performed to evaluate diagnostic performance and associations with clinical parameters.
Results
sST2 levels were significantly higher in the FGR group compared to controls (p = 0.008). In the control group, sST2 levels showed a strong positive correlation with gestational age (r = 0.631, p < 0.001), no such correlation was observed in FGR pregnancies (r = 0.098, p = 0.529). ROC analysis demonstrated moderate diagnostic accuracy of sST2 for FGR (AUC = 0.665, p = 0.004), with high sensitivity (98 %) at a low cut-off (>0.28 ng/ml) and a specificity that reached 90 % at higher thresholds. sST2 also predicted adverse composite neonatal outcomes in FGR cases with an AUC of 0.689.
Discussion
Maternal serum sST2 levels are significantly elevated in FGR pregnancies and may serve as a biomarker for placental dysfunction. Although the sST2 level is not specific enough as a stand-alone diagnostic tool, it can help in risk stratification when used in conjunction with other clinical or biochemical markers.
研究妊娠合并胎儿生长受限（FGR）孕妇血清可溶性抑制致瘤性-2 （sST2）水平，并评估其诊断价值及其与新生儿不良结局的关系。方法本前瞻性观察研究纳入88例单胎妊娠，包括44例FGR病例和44例胎龄匹配的健康对照。使用德尔菲共识标准将FGR分为早发或晚发。采用ELISA法测定妊娠28 ~ 37周孕妇血清sST2水平。进行相关分析和ROC曲线分析，评价诊断效能及其与临床参数的相关性。结果FGR组ssst2水平显著高于对照组（p = 0.008）。在对照组中，sST2水平与胎龄呈正相关（r = 0.631, p < 0.001），在FGR妊娠组中，sST2水平与胎龄无相关性（r = 0.098, p = 0.529）。ROC分析显示，sST2对FGR的诊断准确度中等（AUC = 0.665, p = 0.004），在低临界值（>0.28 ng/ml）下具有高灵敏度（98%），在较高阈值下特异性达到90%。sST2还预测FGR病例的不良综合新生儿结局，AUC为0.689。FGR孕妇血清sST2水平显著升高，可作为胎盘功能障碍的生物标志物。虽然sST2水平作为一种单独的诊断工具不够特异性，但当与其他临床或生化指标结合使用时，它可以帮助进行风险分层。
{"title":"Maternal soluble suppression of Tumorigenicity-2 as a biomarker for fetal growth restriction: Clinical correlations and diagnostic performance","authors":"Sadun Sucu , Sadullah Özkan , Alperen Aksan , Dilara Kurt , Belgin Savran Üçok , Turhan Çağlar","doi":"10.1016/j.placenta.2026.01.004","DOIUrl":"10.1016/j.placenta.2026.01.004","url":null,"abstract":"<div><h3>Introduction</h3><div>To investigate maternal serum levels of soluble suppression of tumorigenicity-2 (sST2) in pregnancies complicated by fetal growth restriction (FGR), and to evaluate its diagnostic utility and association with adverse neonatal outcomes.</div></div><div><h3>Methods</h3><div>This prospective observational study comprised 88 singleton pregnancies, including 44 FGR cases and 44 healthy controls matched for gestational age. FGR was classified as early or late onset using Delphi consensus criteria. Maternal serum sST2 levels were measured between 28 and 37 weeks of gestation by ELISA. Correlation analyzes and ROC curve analyzes were performed to evaluate diagnostic performance and associations with clinical parameters.</div></div><div><h3>Results</h3><div>sST2 levels were significantly higher in the FGR group compared to controls (p = 0.008). In the control group, sST2 levels showed a strong positive correlation with gestational age (r = 0.631, p < 0.001), no such correlation was observed in FGR pregnancies (r = 0.098, p = 0.529). ROC analysis demonstrated moderate diagnostic accuracy of sST2 for FGR (AUC = 0.665, p = 0.004), with high sensitivity (98 %) at a low cut-off (>0.28 ng/ml) and a specificity that reached 90 % at higher thresholds. sST2 also predicted adverse composite neonatal outcomes in FGR cases with an AUC of 0.689.</div></div><div><h3>Discussion</h3><div>Maternal serum sST2 levels are significantly elevated in FGR pregnancies and may serve as a biomarker for placental dysfunction. Although the sST2 level is not specific enough as a stand-alone diagnostic tool, it can help in risk stratification when used in conjunction with other clinical or biochemical markers.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 245-253"},"PeriodicalIF":2.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.placenta.2026.01.002
Lylach Haizler-Cohen , Guisong Wang , Tesfa Dejenie Habtewold , Prabhavi Wijesiriwardhana , Katherine L. Grantz , Fasil Tekola-Ayele
Introduction
Nulliparity is associated with adverse pregnancy outcomes including preeclampsia, preterm birth, lower birth weight and stillbirth although mechanisms are unclear. Placental gene expression differences, which also vary by fetal sex, may drive altered placental function and explain pregnancy outcome differences between nulliparous and multiparous women. This study aims to identify placental gene expression differences based on parity and examine their relationship with birth weight.
Methods
RNA sequencing was performed on placental samples collected at delivery as part of the NICHD Fetal Growth Studies. Differentially expressed genes between placentas of nulliparous (n = 34) and multiparous (n = 41) participants were determined in the full cohort and stratified by fetal sex. Weighted gene co-expression network analysis was performed to identify co-expression modules associated with parity. Correlation of differentially expressed genes and co-expression modules with birth weight was assessed.
Results
Five differentially expressed genes were identified (FDR p < 0.05) including DDX5 (higher expression in multiparas in full cohort), ANKRD33 and SLITRK6 (higher in multiparas in female sub-cohort), and IL1B and MTCO1P40 (higher in nulliparas in female sub-cohort). Two gene co-expression modules, “Grey60” and “Tan”, were negatively associated with multiparity. The DDX5 and ILB1 genes, and the “Grey60” module were significantly correlated with birth weight within the parity group that exhibited lower expression. Genes in the two co-expression modules were enriched for pathways related to immune response, cardiovascular and reproductive system development, and cancer.
Discussion
Placental gene expression differences between nulliparas and multiparas may in part underlie neonatal outcomes that differ by parity and fetal sex.
无产与不良妊娠结局相关，包括先兆子痫、早产、低出生体重和死胎，但机制尚不清楚。胎盘基因表达的差异，也因胎儿性别而异，可能导致胎盘功能的改变，并解释了无产和多产妇女妊娠结局的差异。本研究旨在确定基于胎次的胎盘基因表达差异，并研究其与出生体重的关系。方法对分娩时收集的胎盘样本进行srna测序，作为NICHD胎儿生长研究的一部分。在全队列中，对未产（n = 34）和多产（n = 41）受试者的胎盘差异表达基因进行了测定，并按胎儿性别分层。进行加权基因共表达网络分析，以确定与胎次相关的共表达模块。评估差异表达基因和共表达模块与出生体重的相关性。结果共鉴定出5个差异表达基因（FDR p < 0.05），包括DDX5（在完整队列中多paras中表达较高）、ANKRD33和SLITRK6（在女性亚队列中多paras中表达较高）、IL1B和MTCO1P40（在女性亚队列中无paras中表达较高）。两个基因共表达模块“Grey60”和“Tan”与多胎呈负相关。在低表达胎次组中，DDX5和ILB1基因以及“Grey60”模块与出生体重显著相关。两个共表达模块中的基因丰富，与免疫反应、心血管和生殖系统发育以及癌症相关。无胎和多胎胎盘基因表达的差异可能在一定程度上导致胎次和胎儿性别不同的新生儿结局。
{"title":"Placental gene expression signatures based on maternal parity","authors":"Lylach Haizler-Cohen , Guisong Wang , Tesfa Dejenie Habtewold , Prabhavi Wijesiriwardhana , Katherine L. Grantz , Fasil Tekola-Ayele","doi":"10.1016/j.placenta.2026.01.002","DOIUrl":"10.1016/j.placenta.2026.01.002","url":null,"abstract":"<div><h3>Introduction</h3><div>Nulliparity is associated with adverse pregnancy outcomes including preeclampsia, preterm birth, lower birth weight and stillbirth although mechanisms are unclear. Placental gene expression differences, which also vary by fetal sex, may drive altered placental function and explain pregnancy outcome differences between nulliparous and multiparous women. This study aims to identify placental gene expression differences based on parity and examine their relationship with birth weight.</div></div><div><h3>Methods</h3><div>RNA sequencing was performed on placental samples collected at delivery as part of the NICHD Fetal Growth Studies. Differentially expressed genes between placentas of nulliparous (n = 34) and multiparous (n = 41) participants were determined in the full cohort and stratified by fetal sex. Weighted gene co-expression network analysis was performed to identify co-expression modules associated with parity. Correlation of differentially expressed genes and co-expression modules with birth weight was assessed.</div></div><div><h3>Results</h3><div>Five differentially expressed genes were identified (FDR p < 0.05) including <em>DDX5</em> (higher expression in multiparas in full cohort), <em>ANKRD33</em> and <em>SLITRK6</em> (higher in multiparas in female sub-cohort), and <em>IL1B</em> and <em>MTCO1P40</em> (higher in nulliparas in female sub-cohort). Two gene co-expression modules, “Grey60” and “Tan”, were negatively associated with multiparity. The <em>DDX5</em> and <em>ILB1</em> genes, and the “Grey60” module were significantly correlated with birth weight within the parity group that exhibited lower expression. Genes in the two co-expression modules were enriched for pathways related to immune response, cardiovascular and reproductive system development, and cancer.</div></div><div><h3>Discussion</h3><div>Placental gene expression differences between nulliparas and multiparas may in part underlie neonatal outcomes that differ by parity and fetal sex.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 214-224"},"PeriodicalIF":2.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.placenta.2026.01.003
Jeane Martinha dos Anjos Cordeiro, Bianca Reis Santos, Adriana Lopes da Silva, Luciano Cardoso Santos, Juneo Freitas Silva
Introduction
Proper hormonal signaling at the maternal-fetal interface and adequate placental steroidogenesis are crucial for a successful pregnancy. However, the effects of maternal diabetes (MD) and hypothyroidism (MH) on placental steroidogenic pathways remain poorly characterized. This study investigated the expression of sex hormone receptors and key steroidogenic enzymes at the maternal-fetal interface in rat models of MH and MD.
Methods
At GD18, in both MH (6-propyl-2-thiouracil–induced) and MD (streptozotocin-induced) conditions, maternal hormonal dosage (free T4 or insulin, and E2, P4, and testosterone) were performed, along with placental RT-qPCR and/or immunohistochemistry analyses for steroidogenic pathway markers (ERα/Esr1, PR/Pgr, AR/Ar, Star, Cyp11a1, Hsd17b3, and Hsd3b1).
Results
Both MD and MH dams exhibited reduced fetal weight. These outcomes were associated with elevated plasma estradiol levels in MD rats and reduced testosterone levels in MH rats, while progesterone concentrations remained unchanged in both groups. Both MD and MH resulted in upregulated placental Esr1 expression, whereas MH additionally increased ERα protein levels in the metrial triangle. Regarding the progesterone receptor (PR), MH markedly increased its immunostaining throughout the maternal–fetal interface and both conditions elevated placental Pgr transcript levels. MH also upregulated androgen receptor (AR) protein expression in the decidua and increased placental expression of the steroidogenic enzyme Hsd3b1, while MD elevated placental Ar gene expression.
Conclusion
These findings demonstrate that both MD and, more profoundly, MH disrupt sex steroid homeostasis and receptor expression at the rat maternal–fetal interface.
{"title":"Maternal hypothyroidism and diabetes alter plasma concentration and placental signaling of sex steroids in rats","authors":"Jeane Martinha dos Anjos Cordeiro, Bianca Reis Santos, Adriana Lopes da Silva, Luciano Cardoso Santos, Juneo Freitas Silva","doi":"10.1016/j.placenta.2026.01.003","DOIUrl":"10.1016/j.placenta.2026.01.003","url":null,"abstract":"<div><h3>Introduction</h3><div>Proper hormonal signaling at the maternal-fetal interface and adequate placental steroidogenesis are crucial for a successful pregnancy. However, the effects of maternal diabetes (MD) and hypothyroidism (MH) on placental steroidogenic pathways remain poorly characterized. This study investigated the expression of sex hormone receptors and key steroidogenic enzymes at the maternal-fetal interface in rat models of MH and MD.</div></div><div><h3>Methods</h3><div>At GD18, in both MH (6-propyl-2-thiouracil–induced) and MD (streptozotocin-induced) conditions, maternal hormonal dosage (free T4 or insulin, and E2, P4, and testosterone) were performed, along with placental RT-qPCR and/or immunohistochemistry analyses for steroidogenic pathway markers (ERα/<em>Esr1</em>, PR/<em>Pgr</em>, AR/<em>Ar</em>, <em>Star, Cyp11a1, Hsd17b3</em>, and <em>Hsd3b1</em>).</div></div><div><h3>Results</h3><div>Both MD and MH dams exhibited reduced fetal weight. These outcomes were associated with elevated plasma estradiol levels in MD rats and reduced testosterone levels in MH rats, while progesterone concentrations remained unchanged in both groups. Both MD and MH resulted in upregulated placental <em>Esr1</em> expression, whereas MH additionally increased ERα protein levels in the metrial triangle. Regarding the progesterone receptor (PR), MH markedly increased its immunostaining throughout the maternal–fetal interface and both conditions elevated placental <em>Pgr</em> transcript levels. MH also upregulated androgen receptor (AR) protein expression in the decidua and increased placental expression of the steroidogenic enzyme <em>Hsd3b1</em>, while MD elevated placental <em>Ar</em> gene expression.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that both MD and, more profoundly, MH disrupt sex steroid homeostasis and receptor expression at the rat maternal–fetal interface.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"174 ","pages":"Pages 235-244"},"PeriodicalIF":2.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1016/j.placenta.2026.01.001
YaLu Fu , QiuYan Zhao , YuChan Wang , WeiJing Yang , XingLong Liu , WeiWei Yang , Xin Tan , YuHan Meng
Introduction
Abnormal function of trophoblasts is a primary cause of recurrent spontaneous abortion (RSA). However, the underlying molecular mechanisms remain unclear, and further explanation is urgently needed. This study aims to explore the effect and potential regulatory mechanisms of RANKL in the biological function of trophoblasts.
Methods
Immunohistochemistry was conducted on villous tissues from RSA patients and people who underwent artificial abortion. Cell proliferation, migration, and invasion were assessed in HTR-8/SVneo and JEG-3 cells using CCK-8, scratch wound healing, and transwell assays. Protein expression was analyzed by western blotting.
Results
The expression of RANKL was significantly lower in villus of RSA patients compared to healthy controls. Recombinant human RANKL (rhRANKL) promoted the proliferation, migration and invasion of trophoblasts, while rhOPG, α-RANKL and MK-2206 (Akt inhibitor) alleviated the effect of rhRANK. Moreover, it may exert the effect through the PI3K/Akt signaling pathway.
Conclusions
Our results demonstrated that downregulation of RANKL in villous tissue was associated with RSA, and that it promoted trophoblasts proliferation, invasion, and migration via the PI3K/Akt pathway. This may help elucidate the molecular pathogenesis of impaired embryo adhesion and implantation capacity.
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Microplastics (MPs) are pervasive environmental contaminants increasingly found within human tissues, including the placenta. This study explores the potential of polystyrene (PS)-MPs to cross the placental barrier and their general distribution within term placental chorionic villi explants.
Methods
Term placental chorionic villi explants were exposed up to 72 h to 100 μg/mL of 5 μm-size polystyrene (PS)-MPs, and their internalization was analyzed by optical microscopy, confocal atomic force microscopy (C-AFM) and fluorescence confocal imaging.
Results
The PS-MPs can traverse the placental barrier. Over 72 h of exposure, these particles were not only adsorbed on the surface but also internalized within the syncytiotrophoblast and dispersed through the chorionic villi mesenchyme. Our observations indicate that PS-MPs are found up to 120 μm deep within the villi, suggesting their capability to penetrate deeply into placental tissue. Furthermore, these MPs were surrounded by a thin layer of actin, implying active internalization mechanisms possibly involving macropinocytosis or phagocytosis, although specific pathways in placental tissues remain to be fully elucidated. No evidence of barrier fissures or membrane ruptures was observed, indicating that the internalization process does not disrupt the syncytiotrophoblast barrier integrity.
Discussion
This study underscores the urgent need to understand the implications of such internalization and their effects on placental homeostasis. Given the potential for MPs to influence developmental processes adversely, further research is essential to delineate the mechanisms of MP internalization, possible physiological impacts, and the consequences of fetal exposure.
{"title":"Polystyrene microplastics internalization by term placental chorionic villi explants","authors":"Aldilane Lays Marques , Rodrigo Weingrill , Stephanie Ospina-Prieto , Keyla Pires , Isadora Cavalcante , Ashelley Kettyllem Sousa , Iasmin Cristina Cavalcante , Lais Oliveira , Samuel Souza , Eduardo Jorge Fonseca , Jacob Garcia , Men-Jean Lee , Johann Urschitz , Alexandre Borbely","doi":"10.1016/j.placenta.2025.06.002","DOIUrl":"10.1016/j.placenta.2025.06.002","url":null,"abstract":"<div><h3>Introduction</h3><div><span>Microplastics (MPs) are pervasive environmental contaminants increasingly found within human tissues, including the placenta<span><span>. This study explores the potential of polystyrene (PS)-MPs to cross the </span>placental barrier and their general distribution within term placental </span></span>chorionic villi<span> explants.</span></div></div><div><h3>Methods</h3><div><span>Term placental chorionic villi<span> explants<span> were exposed up to 72 h to 100 μg/mL of 5 μm-size polystyrene (PS)-MPs, and their </span></span></span>internalization<span><span> was analyzed by optical microscopy, confocal </span>atomic force microscopy (C-AFM) and fluorescence confocal imaging.</span></div></div><div><h3>Results</h3><div><span><span><span>The PS-MPs can traverse the placental barrier. Over 72 h of exposure, these particles were not only adsorbed on the </span>surface<span> but also internalized within the syncytiotrophoblast<span> and dispersed through the chorionic villi </span></span></span>mesenchyme<span>. Our observations indicate that PS-MPs are found up to 120 μm deep within the villi, suggesting their capability to penetrate deeply into placental tissue. Furthermore, these MPs were surrounded by a thin layer of actin, implying active internalization mechanisms possibly involving </span></span>macropinocytosis<span><span> or phagocytosis, although specific pathways in placental tissues remain to be fully elucidated. No evidence of barrier fissures or </span>membrane ruptures<span> was observed, indicating that the internalization process does not disrupt the syncytiotrophoblast barrier integrity.</span></span></div></div><div><h3>Discussion</h3><div>This study underscores the urgent need to understand the implications of such internalization and their effects on placental homeostasis. Given the potential for MPs to influence developmental processes adversely, further research is essential to delineate the mechanisms of MP internalization, possible physiological impacts, and the consequences of fetal exposure.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"173 ","pages":"Pages 102-110"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.placenta.2025.04.026
Alejandra María Gómez-Gutiérrez , Angela María Alvarez-Gómez , Juan Carlos Quintana-Castillo , Julio Cesar Bueno-Sánchez , Walter D. Cardona Maya
Preeclampsia (PE) is a hypertensive disorder that generally occurs after the first half of pregnancy, at delivery or even postpartum; it is associated with maternal organ dysfunction and significantly increases maternal, fetal, and newborn morbidity and mortality. During PE, the syncytiotrophoblast and endothelial cells are damaged, and molecules from the extracellular matrix, such as heparan sulfate (HS), can be released into the blood. Therefore, this study aimed to perform a systematic review and meta-analysis to assess the HS levels in serum from women with preeclampsia and normal pregnancy. To perform this systematic review and meta-analysis study, we comprehensively searched PubMed, ScienceDirect and LILACS and collected published studies about HS and preeclampsia. The risk of bias was assessed using the Newcastle-Ottawa Scale score. Upon search completion, 568 studies were identified, and 4 studies were retrieved for the present analysis. The forest plot showed an increase in serum HS in women with preeclampsia relative to non-preeclamptic women, standardized mean diference -SMD-with 95 % CI 1.2 (−0.41 to 2.81), and this relationship is maintained in early PE group (SMD 1.05; 95 % CI (0.22–2.32)). In conclusión, we presented here that HS possibly plays a vital role in the pathogenesis of preeclampsia since the results showed an increase in this molecule's levels in serum from women with preeclampsia.
{"title":"Maternal serum heparan sulfate in preeclampsia pathophysiology: Insights from a systematic review and meta-analysis","authors":"Alejandra María Gómez-Gutiérrez , Angela María Alvarez-Gómez , Juan Carlos Quintana-Castillo , Julio Cesar Bueno-Sánchez , Walter D. Cardona Maya","doi":"10.1016/j.placenta.2025.04.026","DOIUrl":"10.1016/j.placenta.2025.04.026","url":null,"abstract":"<div><div>Preeclampsia (PE) is a hypertensive disorder that generally occurs after the first half of pregnancy, at delivery or even postpartum; it is associated with maternal organ dysfunction and significantly increases maternal, fetal, and newborn morbidity and mortality. During PE, the syncytiotrophoblast and endothelial cells are damaged, and molecules from the extracellular matrix, such as heparan sulfate (HS), can be released into the blood. Therefore, this study aimed to perform a systematic review and meta-analysis to assess the HS levels in serum from women with preeclampsia and normal pregnancy. To perform this systematic review and meta-analysis study, we comprehensively searched PubMed, ScienceDirect and LILACS and collected published studies about HS and preeclampsia. The risk of bias was assessed using the Newcastle-Ottawa Scale score. Upon search completion, 568 studies were identified, and 4 studies were retrieved for the present analysis. The forest plot showed an increase in serum HS in women with preeclampsia relative to non-preeclamptic women, standardized mean diference -SMD-with 95 % CI 1.2 (−0.41 to 2.81), and this relationship is maintained in early PE group (SMD 1.05; 95 % CI (0.22–2.32)). In conclusión, we presented here that HS possibly plays a vital role in the pathogenesis of preeclampsia since the results showed an increase in this molecule's levels in serum from women with preeclampsia.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"173 ","pages":"Pages 63-68"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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