Birth Defects Research最新文献_第2页

Spatial and Temporal Analysis of Hospital Discharges due to Congenital Malformations in Argentina 阿根廷先天性畸形患者出院的时空分析

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-12-01 DOI: 10.1002/bdr2.70001

Marcelo I. Figueroa, Lautaro D. Andrade, Jorge S. López-Camelo, Hernán J. Dopazo, José E. Dipierri

Background

Hospital discharges (HD) provide population data that can be used to define specific epidemiological profiles.

Objectives

To quantify the prevalence of CM among all hospital discharges and its spatiotemporal patterns across Argentina. Furthermore, the study will benchmark these estimates against RENAC to contextualize agreement and discrepancies.

Methods

HD data (2005–2020) from the National Ministry of Health were analyzed at national, regional, and provincial levels. We estimated the proportion of HD due to CM (HDCM; ICD-10 Q00–Q99) overall and by age (< 1 year, 1–5 years, > 5 years). For infants < 1 year, CM prevalence per 100 live births (LB) was computed and compared with RENAC. Temporal trends were assessed with Joinpoint regression.

Results

HDCM represented 0.71% of all HD; 63.4% occurred in children ≥ 1 year, indicating substantial CM-related care beyond infancy. Spatial differences were directionally consistent across sources: nationally and in the Center, RENAC estimates were higher than HDCM; Cuyo showed higher HDCM throughout; NWA shifted to higher HDCM from mid-decade; NEA/Patagonia displayed small gaps with occasional crossovers. Temporally, Joinpoint analyses revealed heterogeneous regional trends without a common timing of inflections: HDCM increased in NWA, the gap widened in Cuyo toward the late decade, while national and Center trajectories were relatively stable; RENAC series remained more tightly clustered around the national pattern. In infants < 1 year, structural cardiac malformations were the leading HD diagnoses.

Conclusion

HD-based metrics and RENAC provide complementary views of the CM burden; their systematic divergence with regional heterogeneity indicates that HD can robustly contextualize spatiotemporal differences where birth-surveillance alone is insufficient.

背景：医院出院（HD）提供可用于定义特定流行病学概况的人口数据。目的：量化CM在阿根廷所有医院出院中的患病率及其时空模式。此外，该研究将根据RENAC对这些估计进行基准测试，以确定一致性和差异。方法：分析国家卫生部2005-2020年的HD数据，包括国家、地区和省级数据。我们估计了CM引起的HD的比例（HDCM; ICD-10 Q00-Q99）总体和年龄（5岁）。结果：HDCM占所有HD的0.71%；63.4%发生在≥1岁的儿童中，表明婴儿期之后有大量与cm相关的护理。不同来源的空间差异在方向上是一致的：在全国和中心，RENAC的估计值高于HDCM；Cuyo全期HDCM增高；NWA从十年中期开始转向更高的HDCM；NEA/巴塔哥尼亚表现出偶尔交叉的小差距。从时间上看，Joinpoint分析揭示了不同区域的不同趋势，没有共同的变化时间：NWA的HDCM增加，Cuyo的差距在近十年中扩大，而全国和中部的轨迹相对稳定；RENAC系列仍然更紧密地聚集在全国范围内。结论：基于hd的指标和RENAC提供了CM负担的互补观点；它们与区域异质性的系统性差异表明，在仅靠出生监测是不够的情况下，HD可以强有力地将时空差异置于背景中。

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引用次数: 0

FGFR1 Tyrosine Kinase Domain Variant p.Val561Met in Caudal Dysraphism: A Case Report FGFR1酪氨酸激酶结构域变异p.Val561Met与尾侧书写障碍的关系：1例报告。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-17 DOI: 10.1002/bdr2.70000

Himanshu Goel, Victoria Yachmenikova, Tanya Mckenny, Hannah Klucknow, Sheridan O'Donnell

Background

Neural tube defects (NTDs) are complex congenital malformations with both environmental and genetic contributions. Monogenic causes of NTDs are increasingly recognized, particularly those involving genes that regulate key morphogenetic pathways. FGFR1, a receptor tyrosine kinase, is crucial for axial and neural development; however, its role in caudal dysraphism remains unclear.

Methods

We report a female fetus delivered at 25 weeks of gestation following prenatal diagnosis of severe lumbosacral spina bifida. Comprehensive postmortem and genetic investigations, including trio exome sequencing, were performed to identify potential causal variants.

Results

Postmortem examination revealed Chiari II malformation, dysmorphic features, bilateral talipes, and a large caudal spinal defect. Trio exome sequencing identified a de novo heterozygous FGFR1 variant (c.1681G>A; p.Val561Met) affecting the conserved tyrosine kinase domain. This variant has been reported in somatic and developmental contexts, where it may modulate FGFR1 signaling, although evidence for constitutive activation remains limited and context-dependent. The variant has not been previously associated with NTD.

Conclusion

This single case raises the possibility that altered FGFR1 signaling may contribute to defective neurulation and warrants further investigation in larger cohorts. Our findings support considering FGFR1 in the differential diagnosis of complex or syndromic spinal dysraphism, though additional evidence is required before recommending its inclusion in routine panels for isolated cases.

背景：神经管缺陷（NTDs）是一种复杂的先天性畸形，与环境和遗传因素有关。人们越来越认识到被忽视热带病的单基因原因，特别是那些涉及调节关键形态发生途径的基因的原因。FGFR1是一种酪氨酸激酶受体，对轴和神经发育至关重要；然而，它在尾侧书写障碍中的作用尚不清楚。方法：我们报告一名女性胎儿在妊娠25周分娩后产前诊断为严重腰骶脊柱裂。全面的死后和遗传调查，包括三重奏外显子组测序，进行了确定潜在的因果变异。结果：尸检显示Chiari II型畸形，畸形特征，双侧taltales和大的尾椎缺损。三人外显子组测序鉴定出一种新的杂合FGFR1变异（c.1681G >a; p.Val561Met），影响保守的酪氨酸激酶结构域。该变体在体细胞和发育环境中已被报道，它可能调节FGFR1信号，尽管构成激活的证据仍然有限且依赖于环境。以前没有发现这种变异与NTD有关。结论：这一单一病例提出了FGFR1信号改变可能导致神经发育缺陷的可能性，值得在更大的队列中进一步研究。我们的研究结果支持在复杂或综合征性脊柱异常的鉴别诊断中考虑FGFR1，尽管在推荐将其纳入孤立病例的常规检查之前需要额外的证据。

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引用次数: 0

Effects of Pre-Conception Stress and Dracocephalum moldavica Extract on Sperm Parameters and Sex Hormones in Parents and Offspring 孕前应激和龙头提取物对亲代和子代精子参数和性激素的影响。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-17 DOI: 10.1002/bdr2.2545

Leila Ghassemifard, Hajar Ramezanikhah, Parisa Jafari, Fatemeh Amiri, Ehsan Saboory

Background

Stress is one of the causes of fertility weakness in both females and males and herbal approaches may reduce this harmful effect. This study aimed to investigate the effect of Dracocephalum moldavica (DM) on the reproductive system in parental pre-pregnancy stress.

Material and Methods

In this experimental study, male and female rats were divided into four groups as follows: control, stress (restraint stress daily for 50 and 15 days for male and female, respectively), extract, and stress + extract. After treatment, the control and experimental rats were mated. Pregnant females were kept undisturbed until delivery and weaning. Offspring were divided into four groups according to the parents’ treatment: McFc, McFc+EX, MsFs, MsFs+EX (M: male, F: female, C: control, S: stress, and EX: extract). Epididymis and vagina were dissected from adult rats; sperm parameters, the thickness of vaginal epithelium, vaginal pH, sex hormone levels were assessed; in pups, testosterone/estradiol, litter size and sex ratio were investigated.

Results

DM extract significantly reduced immotile, dead, and abnormal sperms (p < 0.001) and led to increased levels of testosterone/estradiol in parents and offspring (p < 0.01); the sex ratio was changed among the groups (p = 0.036); the highest number of female pups belonged to the MsFs group. Stress led to a decrease in vaginal thickness and pH while DM extract increased them (p < 0.01).

Conclusion

The results indicate that DM extract may have a beneficial effect on some reproductive parameters affected by pre-conception stress. Notably, it was associated with improvements in sperm quality, hormone levels in parents and offspring, and certain vaginal health measures. Further research is needed to confirm these effects and better understand the underlying mechanisms.

背景：压力是女性和男性生育能力低下的原因之一，草药疗法可以减少这种有害影响。本研究旨在探讨孕前应激对母本生殖系统的影响。材料与方法：本实验将雄性和雌性大鼠分为4组，分别为对照组、应激组（雄性和雌性分别为限制性应激，每天50和15 d）、提取物组和应激+提取物组。治疗后，对照大鼠与实验大鼠进行交配。怀孕的雌性在分娩和断奶前都不受打扰。按亲本处理将子代分为McFc、McFc+EX、MsFs、MsFs+EX 4组（M：雄性，F：雌性，C：对照组，S：应激组，EX：提取物组）。解剖成年大鼠附睾和阴道；评估精子参数、阴道上皮厚度、阴道pH值、性激素水平；对幼犬进行睾酮/雌二醇、产仔数和性别比的研究。结果：DM提取物可显著降低不动、死亡和异常精子(p)。结论：DM提取物可能对孕前应激影响的某些生殖参数有有益作用。值得注意的是，它与精子质量、父母和后代的激素水平以及某些阴道健康措施的改善有关。需要进一步的研究来证实这些影响，并更好地了解潜在的机制。

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引用次数: 0

Understanding Clubfoot: Integrating Historical Origins, Embryologic Foundations, Epidemiology and Etiology—A Review 了解内翻足：整合历史起源、胚胎学基础、流行病学和病因学综述

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-15 DOI: 10.1002/bdr2.2543

J. S. R. G. Saran, Varun Devdass, Durai Anand

Purpose

Congenital talipes equinovarus (CTEV) or idiopathic clubfoot, is a common yet complex congenital musculoskeletal deformity characterized by cavus, adductus, varus and equinus components. Despite advances in conservative and surgical management, recurrence and long-term functional limitations remain unresolved challenges. This review aims to provide an integrative synthesis of the historical evolution, embryological basis, etiological theories and clinical implications of idiopathic clubfoot.

Methods

A narrative literature review was conducted, synthesizing data from historical records, embryological studies, genetic and developmental biology research and clinical reports. Key theories of etiology, including embryological, genetic, vascular, neuromuscular, environmental and structural mechanisms, were critically examined to highlight converging and divergent perspectives.

Results

The evidence suggests that idiopathic clubfoot arises from a multifactorial interplay of genetic predisposition, aberrant embryological signaling pathways, vascular dysgenesis, and environmental influences. While molecular studies implicate PITX1–TBX4 pathways and extracellular matrix remodeling, developmental hypotheses highlight disruptions in muscle patterning, connective tissue organization and vascular development. Clinically, even well-corrected cases demonstrate persistent sequelae such as restricted ankle mobility, muscle weakness and altered biomechanics, predisposing to early degenerative joint changes.

Conclusions

CTEV should be considered a systemic developmental dysplasia rather than an isolated foot deformity. The persistence of recurrence and long-term morbidity underscores the need for multidisciplinary research integrating genetics, developmental biology, biomechanics and rehabilitation. Improved understanding of the etiological mechanisms may enable earlier detection, targeted interventions and ultimately better long-term outcomes for affected individuals.

先天性马蹄内翻（CTEV）或特发性内翻足，是一种常见但复杂的先天性肌肉骨骼畸形，其特征是腔窝、内收、内翻和马蹄成分。尽管保守和手术治疗取得了进展，但复发和长期功能限制仍然是未解决的挑战。本文综述了特发性内翻足的历史演变、胚胎学基础、病因学理论和临床意义。方法综合历史文献、胚胎学研究、遗传与发育生物学研究及临床报告等资料，进行文献综述。病因学的关键理论，包括胚胎学，遗传学，血管，神经肌肉，环境和结构机制，严格审查，以突出趋同和分歧的观点。结果有证据表明特发性内翻足是遗传易感性、胚胎信号通路异常、血管发育不良和环境影响等多因素相互作用的结果。虽然分子研究涉及PITX1-TBX4通路和细胞外基质重塑，但发育假说强调肌肉模式，结缔组织组织和血管发育的破坏。临床上，即使矫正良好的病例也会出现持续的后遗症，如踝关节活动受限、肌肉无力和生物力学改变，易发生早期退行性关节变化。结论CTEV应被认为是一种全身性发育不良，而不是孤立的足部畸形。复发的持久性和长期发病率强调需要多学科研究整合遗传学，发育生物学，生物力学和康复。提高对病因机制的了解可能有助于早期发现、有针对性的干预，并最终为受影响的个体带来更好的长期结果。

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引用次数: 0

Pregnancy Outcomes Following Paternal Methotrexate Exposure: A Systematic Review and Meta-Analysis 甲氨蝶呤暴露后的妊娠结局：一项系统回顾和荟萃分析

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-14 DOI: 10.1002/bdr2.2542

Nusret Uysal, Hüseyin Yilmaz, Mesut Gungor, Ahmet Ozyurek, Tijen Kaya-Temiz, Baris Karadas, Yusuf C. Kaplan

Objective

Evidence guiding the management of pregnancies fathered by men exposed to methotrexate (MTX) remains limited. This systematic review and meta-analysis evaluated whether paternal MTX exposure before or at conception is associated with major congenital malformations or other adverse pregnancy outcomes.

Data Sources

PubMed, Web of Science, and Reprotox were searched from inception to May 2025, supplemented by manual reference screening.

Study Eligibility Criteria

Eligible studies were cohort or case–control designs assessing paternal MTX exposure during preconception or conception period with an unexposed control group. Reviews, editorials, animal studies, case reports, and overlapping datasets were excluded.

Methods

Study selection and data extraction were conducted independently. Risk of bias was assessed with ROBINS-I, quality with the Newcastle-Ottawa Scale, and certainty of evidence with GRADE. Adjusted odds ratios (aORs) were used for random-effects meta-analysis; outcomes lacking sufficient data were narratively synthesized. The primary outcome was major congenital malformations following paternal MTX exposure. Secondary outcomes included cardiac malformations, spontaneous abortion, live birth, elective termination, stillbirth, and preterm birth.

Results

No increased risks were observed for congenital malformations (aOR 1.00; 95% CI 0.62–1.61; I² = 0%), stillbirth (OR 0.85; 95% CI 0.11–6.45; I² = 0%), or preterm birth (OR 0.95; 95% CI 0.59–1.53; I² = 26%). In the qualitative review of case reports, case series, and noncomparable cohort data, no consistent or recurring patterns of malformations were identified.

Conclusions

Paternal MTX exposure was not associated with increased risks of congenital malformations, stillbirth, or preterm birth, nor with a consistent or recurrent pattern of anomalies. These findings provide reassurance regarding fetal safety following paternal MTX exposure.

客观证据指导管理的男性接触甲氨蝶呤（MTX）的怀孕仍然有限。本系统综述和荟萃分析评估了父亲在怀孕前或怀孕时接触甲氨蝶呤是否与主要先天性畸形或其他不良妊娠结局有关。数据来源PubMed， Web of Science和Reprotox从成立到2025年5月进行检索，并辅以人工参考筛选。符合条件的研究是队列或病例对照设计，评估父亲在孕前或受孕期与未暴露对照组的甲氨蝶呤暴露。综述、社论、动物研究、病例报告和重叠数据集被排除在外。方法独立进行研究选择和资料提取。偏倚风险采用ROBINS-I评估，质量采用Newcastle-Ottawa量表评估，证据确定性采用GRADE评估。随机效应荟萃分析采用调整优势比（aORs）；缺乏足够数据的结果被叙述合成。主要结果是父亲接触甲氨蝶呤后的主要先天性畸形。次要结局包括心脏畸形、自然流产、活产、选择性终止妊娠、死产和早产。结果先天性畸形（aOR 1.00; 95% CI 0.62-1.61; I2 = 0%）、死产（aOR 0.85; 95% CI 0.11-6.45; I2 = 0%）和早产（aOR 0.95; 95% CI 0.59-1.53; I2 = 26%）的风险均未增加。在病例报告、病例系列和不可比较的队列数据的定性回顾中，没有确定一致或反复出现的畸形模式。结论：父亲甲氨蝶呤暴露与先天性畸形、死产或早产的风险增加无关，也与持续或复发的异常模式无关。这些发现为父亲接触甲氨蝶呤后胎儿的安全提供了保证。

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引用次数: 0

Infant Mortality due to Congenital Diaphragmatic Hernia, United States 2007–2021 美国2007-2021年先天性膈疝导致的婴儿死亡率。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-12 DOI: 10.1002/bdr2.2544

Ramesh Vidavalur, Kanekal S. Gautham

Objective

To analyze temporal trends and geographic variations in infant mortality rate associated with congenital diaphragmatic hernia (CDH-IMR) in the United States.

Methods

From 2007 to 2021, we used CDC-WONDER linked birth/death data to identify CDH-related infant deaths (ICD-10 code: Q79 as the underlying cause of death), analyze annual CDH-IMR trends, and explore associations with sex, gender, gestational age (GA), and U.S. state of birth. Descriptive statistics were derived, and bivariate analyses were conducted to discern differences in CDH-IMR by gender, race, and GA. CDH-IMR was expressed per 100,000 live births with Poisson-modeled 95% confidence intervals, and trends were assessed through joinpoint regression to extrapolate annual percent change (APC).

Results

Between 2007 and 2021, 59,117,761 live births and 3391 CDH-related infant deaths were recorded. CDH infant deaths accounted for 0.96% of all infant deaths and occurred in 0.006% of live births. The mean CDH-IMR was 5.7 (95% CI: 5.5–5.9) per 100,000 live births, with a significant downward trend (APC: −1.3%, [95% CI: −2.0, −0.5, p < 0.01]). Asian infants had a lower risk of mortality (RR 0.66 [95% CI: 0.55, 0.79]) compared to White infants, and higher GA at birth correlated with better survival. Regional analysis revealed a median CDH-IMR (IQR) of 5.9 (4.7, 7.2), with a three-fold variation across U.S. states.

Conclusion

In this national population-based U.S. study, we observed a decreasing trend in CDH-IMR. However, significant variation in CDH mortality persists by region, gender, and race. Despite evidence of current CDH care is associated with a decreasing trend in mortality, there remain many opportunities for equitable improvement in outcomes across race, gender and by geographic region.

目的：分析美国先天性膈疝（CDH-IMR）相关婴儿死亡率的时间趋势和地理差异。方法：从2007年到2021年，我们使用CDC-WONDER相关的出生/死亡数据来确定与cdh相关的婴儿死亡（ICD-10代码：Q79作为潜在死亡原因），分析年度CDH-IMR趋势，并探讨与性别、性别、胎龄（GA）和美国出生状态的关系。导出描述性统计数据，并进行双变量分析，以辨别性别、种族和遗传基因在CDH-IMR中的差异。用泊松模型的95%置信区间表示每10万活产婴儿的CDH-IMR，并通过联点回归来推断年百分比变化（APC）来评估趋势。结果：2007年至2021年期间，记录了59,117,761例活产和3391例与冠心病相关的婴儿死亡。婴儿死亡占所有婴儿死亡的0.96%，占活产婴儿的0.006%。平均CDH-IMR为每10万例活产5.7例（95% CI: 5.5-5.9），呈显著下降趋势（APC: -1.3%, [95% CI: -2.0, -0.5, p]）。结论：在这项基于美国全国人群的研究中，我们观察到CDH-IMR呈下降趋势。然而，CDH死亡率在地区、性别和种族之间存在显著差异。尽管有证据表明，目前的CDH护理与死亡率下降趋势有关，但仍有许多机会可以公平地改善跨种族、性别和地理区域的结果。

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引用次数: 0

Expression Pattern Alterations of the Brain KCC2 Chloride Transporter in Male Rats Following Postnatal Extremely Low-Frequency Electromagnetic Field Exposure Associated With Behavioral Outcomes 极低频电磁场暴露后雄性大鼠脑KCC2氯转运体表达模式的改变与行为结果的关系

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-11 DOI: 10.1002/bdr2.2546

Mozhdeh Nemati, Masoumeh Nozari, Fatemeh Darvishzadeh-Mahani, Meysam Ahmadi-Zeidabadi, Sepideh Ganjalikhan-hakemi, Hamideh Bashiri, Sara Haratizadeh

Background

Exposure to extremely low-frequency magnetic fields (ELF-MFs) has increased with technological development. Environmental factors are known to influence the K⁺–Cl⁻ cotransporter 2 (KCC2), which regulates neuronal chloride homeostasis and is essential for brain development through its role in the GABAergic shift. In this study, we investigated the effects of ELF-MF exposure on KCC2 expression and related behavioral and biochemical outcomes in Wistar rat pups.

Methods

Wistar rat pups were exposed to ELF-MF (10 mT, 50 Hz) for 2 h per day from postnatal day (PND) 1 to 10.

Results

Results indicated a significant reduction in KCC2 expression in the ELF-MF–exposed group. Furthermore, these animals exhibited enhanced anxiety-like behaviors, elevated brain malondialdehyde (MDA) levels, and shortened latency to tonic–clonic seizures compared with controls.

Conclusions

These findings suggest that early exposure to ELF-MFs disrupts KCC2 expression in the developing brain and induces behavioral and biochemical abnormalities in male rats.

背景：随着技术的发展，暴露于极低频磁场（ELF-MFs）的情况越来越多。已知环境因素会影响K+- cl -共转运蛋白2 (KCC2)， KCC2调节神经元氯离子稳态，并通过其在gaba能转移中的作用对大脑发育至关重要。在这项研究中，我们研究了ELF-MF暴露对Wistar大鼠幼鼠KCC2表达及其相关行为和生化结果的影响。方法：Wistar大鼠幼仔从出生后第1天至第10天，每天暴露2小时（10 mT, 50 Hz） ELF-MF。结果：结果显示，elf - mf暴露组KCC2表达明显降低。此外，与对照组相比，这些动物表现出焦虑样行为增强，脑丙二醛（MDA）水平升高，强直阵挛发作潜伏期缩短。结论：这些发现表明，早期暴露于ELF-MFs会破坏发育中的雄性大鼠大脑中KCC2的表达，并诱导行为和生化异常。

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引用次数: 0

Maternal and Placental Inflammation Influence Formation of Neural Tube Defects in Quaternary Ammonium Compound Exposed Mice 母体和胎盘炎症对季铵化合物暴露小鼠神经管缺损形成的影响。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-05 DOI: 10.1002/bdr2.2539

Justin Kula, Ryan P. Seguin, Libin Xu, Dylan Davis, Sarah E. Payne, Chad E. Byrd, Terry C. Hrubec

Background

Quaternary ammonium compounds (QACs) are common chemicals used for their antimicrobial, antistatic, and surfactant properties. Two common QACs, alkyldimethylbenzyl ammonium chloride (ADBAC or BAC) and didecyldimethyl ammonium chloride (DDAC), cause neural tube defects (NTDs) in mice and are proinflammatory in both mice and humans. The maternal immune system plays an integral role in normal fetal development with cytokine mediators in the placenta directing both placental and fetal development. This study was conducted to determine whether maternal systemic or placental inflammation was involved in QAC-induced NTDs.

Methods

Pregnant CD-1 mice received either a single gavage dose on gestational day (GD) 8.5; two gavage doses, one on GD 7.5 and the other on GD 8.5; or were dosed in the feed prior to mating and throughout breeding and gestation. Maternal whole blood, maternal bone marrow-derived macrophages, placentas, GD 10.5 embryos, and GD 17.5 fetuses were collected for NTD, cytokine and QAC analysis. Cytokines IL-6, IL-10, IL-12, PlGF, and TNF-α were determined by ELISA. ADBAC and DDAC concentrations were determined by UPLC–MS/MS.

Results

ADBAC and DDAC concentrated in placental tissue. Placentas from exposed pregnancies demonstrated increased production of inflammatory IL-10, IL-6, and TNF-α in embryo–placental units with NTDs. Inflammatory IL-10, anti-inflammatory IL-10, IL-6, and TNF-α were increased in macrophages isolated from QAC-exposed mothers, and plasma IL-6, and TNF-α were correlated with NTDs.

Conclusion

The placenta is the target tissue for ADBAC and DDAC-induced teratogenicity. Both placental inflammation and maternal systemic inflammation are likely involved in QAC-induced NTD formation in mice.

背景：季铵化合物（QACs）因其抗菌、抗静电和表面活性剂的特性而被广泛使用。两种常见的QACs，烷基二甲基苄基氯化铵（ADBAC或BAC）和二烷基二甲基氯化铵（DDAC），在小鼠中引起神经管缺陷（NTDs），并且在小鼠和人类中都具有促炎作用。母体免疫系统在正常胎儿发育中起着不可或缺的作用，胎盘中的细胞因子介质指导胎盘和胎儿的发育。本研究旨在确定qac诱导的NTDs是否与母体全身性或胎盘性炎症有关。方法：妊娠期CD-1小鼠在妊娠日（GD） 8.5单次灌胃；两剂灌胃，一剂在GD 7.5，一剂在GD 8.5；或在交配前和整个繁殖和妊娠期间在饲料中添加。采集母胎全血、母胎骨髓源性巨噬细胞、胎盘、GD 10.5胚胎、GD 17.5胎儿进行NTD、细胞因子和QAC分析。ELISA法检测细胞因子IL-6、IL-10、IL-12、PlGF、TNF-α。采用UPLC-MS/MS法测定ADBAC和DDAC浓度。结果：ADBAC和DDAC均在胎盘组织中富集。暴露妊娠的胎盘在NTDs的胚胎-胎盘单位中显示炎症性IL-10、IL-6和TNF-α的产生增加。qac暴露母鼠巨噬细胞中炎性IL-10、抗炎IL-10、IL-6和TNF-α升高，血浆IL-6和TNF-α与NTDs相关。结论：胎盘是ADBAC和ddac致致畸的靶组织。胎盘炎症和母体全身性炎症都可能参与qac诱导的小鼠NTD形成。

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引用次数: 0

Maternal Immune Stimulation With Interferon-Gamma Limits Embryonic Valproic Acid Induced Apoptotic Gene Expression 干扰素- γ母体免疫刺激限制胚胎丙戊酸诱导的凋亡基因表达。

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-11-05 DOI: 10.1002/bdr2.2541

Daniel Frascella, Murali K. Mallela, Robert Cullen, Terry C. Hrubec

Background

Neural tube defects (NTDs) are developmental malformations affecting 1300 newborns in the United States each year. Valproic acid (VA), a drug to treat seizures and mood disorders, can cause NTDs. Apoptosis is increased in the developing neural tubes (NTs) of embryos exposed to VA thereby identifying a possible mechanism for NTD formation. Numerous studies show that maternal immune stimulation (MIS) in the periconceptual period reduces birth defects including VA-induced NTDs. It is hypothesized that immunoregulatory cytokines may normalize the dysregulated apoptosis. This study examined maternal cytokine production and embryonic apoptotic gene expression following prebreeding stimulation with interferon-γ (IFN-γ) and gestational VA exposure.

Methods

Concentrations of granulocyte monocyte colony stimulating factor (GM-CSF), IFN-γ, interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNFα) were determined in VA + IFN-γ-treated pregnant mice. Expression of pro-apoptotic and antiapoptotic pathway genes was determined in VA and VA + IFN-γ exposed embryos.

Results

NTDs decreased from 45.3% to 21.2% per litter with MIS. MIS altered the profiles of GM-CSF and IFN-γ throughout pregnancy and altered the profiles of GM-CSF, IL-6, and IL-10 over the time of NT closure. Pro-apoptotic genes were upregulated, and anti-apoptotic genes were downregulated in VA-exposed embryonic heads with open or closed NTs. Gene expression was normalized with VA + IFN-γ in embryonic heads with closed NTs.

Conclusion

This study identified GM-CSF and IFN-γ as possible effectors of MIS and specifically GM-CSF, IL-6, and IL-10 in preventing NTDs. MIS normalized apoptotic gene expression in embryos with closed NTs identifying a possible molecular mechanism for the prevention of VA-induced NTDs.

背景：神经管缺陷（NTDs）是一种发育畸形，在美国每年影响1300名新生儿。丙戊酸（VA）是一种治疗癫痫发作和情绪障碍的药物，可导致被忽视的热带病。暴露于VA的胚胎发育中的神经管（NTs）细胞凋亡增加，从而确定了NTD形成的可能机制。大量研究表明，围孕期母体免疫刺激（MIS）可减少出生缺陷，包括va诱导的NTDs。假设免疫调节细胞因子可能使失调的细胞凋亡正常化。本研究检测了干扰素-γ (IFN-γ)和妊娠期VA刺激后母体细胞因子的产生和胚胎凋亡基因的表达。方法：测定VA + IFN-γ处理的妊娠小鼠粒细胞单核细胞集落刺激因子（GM-CSF）、IFN-γ、白细胞介素-6 （IL-6）、白细胞介素-10 （IL-10）和肿瘤坏死因子-α (tnf -α)的浓度。测定VA和VA + IFN-γ暴露胚胎中促凋亡和抗凋亡通路基因的表达。结果：每窝新生儿NTDs由45.3%下降至21.2%。MIS在整个妊娠期间改变了GM-CSF和IFN-γ的谱，并在NT关闭期间改变了GM-CSF、IL-6和IL-10的谱。在打开或关闭NTs的va暴露的胚胎头中，促凋亡基因上调，抗凋亡基因下调。在NTs闭合的胚胎头中，用VA + IFN-γ使基因表达正常化。结论：本研究确定GM-CSF和IFN-γ可能是MIS的效应器，特别是GM-CSF、IL-6和IL-10在预防NTDs中的作用。MIS使关闭NTs的胚胎中凋亡基因表达正常化，确定了预防va诱导的ntd的可能分子机制。

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引用次数: 0

A Case Report: Co-Occurrence of TNRC6B Gene Variant and Xq28 Microdeletion Syndrome With Comprehensive Literature Review TNRC6B基因变异与Xq28微缺失综合征共现1例并文献综述

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2025-10-28 DOI: 10.1002/bdr2.2521

Ying Deng, Chenchen Bu, Zhuoma Basang, Quzhen Zhaxi

Background

TNRC6B encodes a protein crucial for RNA silencing, and heterozygous variants of TNRC6B have been associated with developmental delay/intellectual disability, speech and language delay, fine and motor delay, and a range of neurobehavioral phenotypes, including autism and attention deficit and hyperactivity disorder (ADHD). Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting girls, characterized by loss of acquired speech and motor skills, repetitive hand movements, breathing irregularities, seizures, and is a prevalent cause of intellectual disability in females. Most RTT cases are due to pathogenic variants in the MECP2 gene located at Xq28, encoding methyl-CpG binding protein 2 (MeCP2). The phenotypic spectrum of heterozygous TNRC6B variants combined with MECP2 gene deletion has not been well described.

Case Presentation

A 17-month-old Chinese female patient with severe malnutrition and global developmental delay (GDD) was enrolled in this study. Whole-exome sequencing was conducted, and clinical data were obtained retrospectively from medical history and formal neuropsychological evaluation. The heterozygous TNRC6B variants (c.1409A > G; p.Asp470Ser) and a 4.066 Kb intragenic deletion of Xq28 encompassing the MECP2 gene were found. This expands the genetic spectrum of TNRC6B variants. The patient exhibited GDD, behavioral abnormalities, stunting, underweight, microcephaly and facial dysmorphism, including low-set ears, wide-set eyes, upslanting lateral canthi, underbite and hypertonia. The patient has received feeding guidance and rehabilitation training, and is currently under regular follow-up. This case broadens the phenotypic spectrum associated with TNRC6B variants and MECP2 gene deletion.

Conclusion

This is the first report of a Xq28 microdeletion encompassing the MECP2 gene combined with heterozygous variants in TNRC6B. Our study expands the genotypic and phenotypic spectrum of TNRC6B deficiency syndrome and Rett syndrome. Our findings suggest that patients with TNRC6B and MECP2 gene deficiencies may experience more severe developmental delay and malnutrition.

TNRC6B编码一种对RNA沉默至关重要的蛋白质，TNRC6B的杂合变异与发育迟缓/智力残疾、言语和语言迟缓、精细和运动迟缓以及一系列神经行为表型相关，包括自闭症、注意缺陷和多动障碍（ADHD）。Rett综合征（RTT）是一种主要影响女孩的神经发育障碍，其特征是丧失获得性语言和运动技能、手部重复运动、呼吸不规则、癫痫发作，是女性智力残疾的普遍原因。大多数RTT病例是由于位于Xq28的MECP2基因的致病性变异，该基因编码甲基- cpg结合蛋白2 （MECP2）。杂合子TNRC6B变异合并MECP2基因缺失的表型谱尚未得到很好的描述。本研究选取了一名17个月大的严重营养不良和全面发育迟缓（GDD）的中国女性患者。进行全外显子组测序，并从病史和正式的神经心理学评估中回顾性获得临床资料。发现TNRC6B杂合变异体（c.1409A >； G; p.Asp470Ser）和包含MECP2基因的Xq28基因内缺失4.066 Kb。这扩大了TNRC6B变异的遗传谱。患者表现为GDD、行为异常、发育迟缓、体重不足、小头畸形和面部畸形，包括低耳、宽眼、侧眦上斜、下咬合和高张力。患者已接受喂养指导和康复训练，目前正在定期随访。该病例拓宽了与TNRC6B变异和MECP2基因缺失相关的表型谱。这是首次报道TNRC6B中包含MECP2基因的Xq28微缺失并伴有杂合变异体。本研究扩大了TNRC6B缺乏症和Rett综合征的基因型和表型谱。我们的研究结果表明，TNRC6B和MECP2基因缺失的患者可能会经历更严重的发育迟缓和营养不良。

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引用次数: 0