Birth Defects Research最新文献_第8页

Folic acid supplementation in women of childbearing age with epilepsy: Missing the forest for the trees? 为患有癫痫的育龄妇女补充叶酸：只见树木，不见森林？

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-06-05 DOI: 10.1002/bdr2.2332

Alain Braillon

引用次数: 0

Rodent anogenital distance recommendations 啮齿动物肛门距离建议。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-06-01 DOI: 10.1002/bdr2.2347

L. David Wise

Background

Measurement of rat anogenital distance (AGD) dates to at least 1912. Increased interest in endocrine disrupting chemicals and the use of AGD as a biomarker for fetal androgen effects have increased the number of studies with this endpoint in recent decades. A literature review revealed different landmarks, methods of measurement, and methods to adjust for body weight differences. AGD is often reported to hundredths of millimeters and as such, deserves precision in all these aspects. This paper presents recommendations for the measurement and analysis of rodent AGD.

Methods

Literature and regulatory guidance documents that mentioned or measured rodent AGD were reviewed. Four adjustment methods were evaluated using available online data from three rat studies each with two generations of offspring.

Results

Tabulation of studies reveals that species/stocks and time of data collection, but more importantly anatomical landmarks and methods of measurement have produced a variety of results which are difficult to compare. Not all studies have adjusted for test article effects on body weight (and thus size). The four adjustment methods were fairly comparable.

Conclusion

Recommendations are as follows. A microscopic method should be used to measure AGD of late rodent fetuses and early postnatal pups. The caudal edge of the genital tubercle and the cranial edge of the anus are clear and identifiable landmarks. The simplest adjustment is to divide individual AGDs by the cube root of animals’ body weight. These recommendations will help ensure data consistency and accuracy, and facilitate meaningful comparisons across laboratories and chemical classes.

背景：对大鼠肛门距离（AGD）的测量至少可以追溯到 1912 年。近几十年来，人们对干扰内分泌的化学物质越来越感兴趣，并将 AGD 用作胎儿雄激素影响的生物标志物，从而增加了对这一终点的研究数量。文献综述显示了不同的地标、测量方法和调整体重差异的方法。AGD 通常以百分之一毫米为单位进行报告，因此在所有这些方面都需要精确。本文提出了测量和分析啮齿动物 AGD 的建议：方法：查阅了提及或测量啮齿动物 AGD 的文献和监管指导文件。利用三项大鼠研究的在线数据对四种调整方法进行了评估，每项研究都包含两代后代：研究列表显示，物种/种群和数据收集时间，但更重要的是解剖标志物和测量方法，产生了难以比较的各种结果。并非所有研究都对试验品对体重（以及体型）的影响进行了调整。四种调整方法具有相当的可比性：建议如下应使用显微镜方法测量啮齿类晚期胎儿和出生后早期幼鼠的 AGD。生殖器结节的尾缘和肛门的颅缘是清晰可辨的地标。最简单的调整方法是将单个 AGD 除以动物体重的立方根。这些建议将有助于确保数据的一致性和准确性，并有助于在不同实验室和化学类别之间进行有意义的比较。

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引用次数: 0

Absent or hypoplastic nasal bone: What to tell the prospective parents? 鼻骨缺失或发育不良：如何告诉未来的父母？

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-27 DOI: 10.1002/bdr2.2348

Shreya Das, Charu Sharma, Taruna Yadav, Kalika Dubey, Shashank Shekhar, Pratibha Singh, Kuldeep Singh, Meenakshi Gothwal, Manisha Jhirwal, Dolat Singh Shekhawat

Background

Absent or hypoplastic nasal bone (AHNB) on first or second-trimester ultrasonography (USG) is an important soft marker of Down syndrome. However, due to its varied incidence in euploid and aneuploid fetuses, there is always a dilemma of whether to go for invasive fetal testing for isolated AHNB. This study aims to assess outcomes specifically within the context of Indian ethnicity women.

Materials and Methods

This was a prospective observational study. All patients who reported with AHNB in the first- or second-trimester USG were included. Genetic counseling was done, and noninvasive and invasive testing was offered. Chromosomal anomalies were meticulously recorded, and pregnancy was monitored.

Results

The incidence of AHNB in our study was 1.16% (47/4051). Out of 47 women with AHNB, the isolated condition was seen in 32 (0.78%) cases, while AHNB with structural anomalies was seen in nine cases (0.22%). Thirty-nine women opted for invasive testing. Six out of 47 had aneuploidy (12.7%), while two euploid cases (4.25%) developed nonimmune hydrops. The prevalence of Down syndrome in fetuses with AHNB was 8.5% (4/47) and 0.42% (17/4004) in fetuses with nasal bone present. This difference was statistically significant (p = .001).

Conclusion

The results indicate that isolated AHNB cases should be followed by a comprehensive anomaly scan rather than immediately recommending invasive testing. However, invasive testing is required when AHNB is associated with other soft markers or abnormalities. As chromosomal microarray is more sensitive than standard karyotype in detecting chromosomal aberrations, it should be chosen over karyotype.

背景：第一或第二孕期超声造影（USG）显示的鼻骨缺失或鼻骨发育不良（AHNB）是唐氏综合征的重要软标志物。然而，由于其在优倍体和非整倍体胎儿中的发生率不同，是否对孤立的鼻骨缺失进行侵入性胎儿检测始终是一个两难选择。本研究旨在评估印度裔妇女的具体结果：这是一项前瞻性观察研究。所有在第一或第二孕期 USG 中报告有 AHNB 的患者均被纳入研究。对患者进行遗传咨询，并提供无创和有创检测。对染色体异常进行了详细记录，并对妊娠进行了监测：在我们的研究中，AHNB 的发生率为 1.16%（47/4051）。在 47 名患有 AHNB 的妇女中，32 例（0.78%）为单独病例，9 例（0.22%）为 AHNB 伴有结构异常。39 名妇女选择了侵入性检查。47 例中有 6 例（12.7%）为非整倍体，2 例（4.25%）为优生体质，患上了非免疫性肾积水。患有 AHNB 的胎儿中唐氏综合征的发生率为 8.5%（4/47），而鼻骨存在的胎儿中唐氏综合征的发生率为 0.42%（17/4004）。这一差异具有统计学意义（P = .001）：结果表明，孤立的 AHNB 病例应进行全面异常扫描，而不是立即建议进行有创检查。然而，当 AHNB 与其他软标记物或异常相关联时，则需要进行侵入性检测。由于染色体微阵列在检测染色体畸变方面比标准核型更敏感，因此应选择染色体微阵列而不是核型。

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引用次数: 0

Potential risk factors for hypospadias and negative correlation with DICER1 (rs3742330) A>G variant in Algerian population: A case-control study 阿尔及利亚人群尿道下裂的潜在风险因素及与 DICER1 (rs3742330) A>G 变异的负相关：病例对照研究。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-27 DOI: 10.1002/bdr2.2365

Laouar Rania, Chellat Djalila, Djoudi Brahim, Achou Rayene, Horchi Meroua, Touabti Souhem, Atrih Zoubir, Choutri Hichem, Boukri Asma, Satta Dalila, Sifi Karima

Background

Hypospadias continues to be a prevalent congenital anomaly affecting the male external genitalia, characterized by an unclear origin and complex treatment approaches. This study aimed to investigate the risk factors associated with hypospadias and explore its genetic link with the DICER1 rs3742330 variant.

Methods

The study involved two groups: 105 male children with hypospadias and 111 healthy male children as matched controls. Detailed history and physical examinations were conducted for all patients and controls. PCR-restriction fragment length polymorphism was utilized to identify the DICER1 rs3742330 variant, analyzing genotype distribution and allele frequency. Logistic regression analysis estimated the risk factors for hypospadias.

Results

The mean age in the hypospadias group was 4.56 ± 2.50 years. The most prevalent type of hypospadias observed was the anterior type in 60 children (57.14%). Intrauterine growth restriction, advanced maternal age, and gestational hypertension were identified as significant risk factors for hypospadias (p = .011, p = .016, and p = .041, respectively). Regarding the genetic study, no significant difference was found in both genotype and allele frequencies of the DICER1 rs3742330 variant between case and control groups.

Conclusions

The rs3742330 variant in the DICER1 gene showed no association with hypospadias cases in the Algerian population. However, multivariate logistic regression analysis identified preterm birth, low birth weight, intrauterine growth restriction, advanced maternal age, gestational diabetes, and rural residence as the most significant independent predictors for hypospadias.

背景：尿道下裂仍然是影响男性外生殖器的一种常见先天性畸形，其特点是病因不明，治疗方法复杂。本研究旨在调查尿道下裂的相关风险因素，并探讨其与 DICER1 rs3742330 变异的遗传联系：研究包括两组：105 名尿道下裂男童和 111 名健康男童作为匹配对照。对所有患者和对照组进行了详细的病史和体格检查。利用PCR-限制性片段长度多态性鉴定DICER1 rs3742330变异，分析基因型分布和等位基因频率。逻辑回归分析估计了尿道下裂的风险因素：尿道下裂患者的平均年龄为（4.56 ± 2.50）岁。尿道下裂最常见的类型是前尿道下裂，有 60 名患儿（57.14%）。宫内生长受限、高龄产妇和妊娠高血压被认为是尿道下裂的重要风险因素（分别为 p = .011、p = .016 和 p = .041）。在基因研究方面，病例组和对照组的 DICER1 rs3742330 变体的基因型和等位基因频率均无明显差异：结论：在阿尔及利亚人群中，DICER1 基因 rs3742330 变体与尿道下裂病例没有关联。然而，多变量逻辑回归分析发现，早产、低出生体重、宫内生长受限、高龄产妇、妊娠糖尿病和农村居民是尿道下裂最重要的独立预测因素。

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引用次数: 0

In vitro fertilization and pregnancy outcomes of women with X chromosome abnormality: A case series X 染色体异常妇女的体外受精和妊娠结局：病例系列。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-23 DOI: 10.1002/bdr2.2349

Ruohan Wang, Linyu Zhang, Jia Liao, Fang Ma, Qianhong Ma

Background

To describe and conclude the in vitro fertilization (IVF) results of patients with X chromosome abnormality.

Methods

A retrospective case series was conducted. According to the number of normal X, patients were allocated into two groups: Group A (patients with only a normal X, while other X has any types of abnormalities) and Group B (patients have two or more normal X chromosomes). Clinical data, including basic information, fertility information, and IVF outcomes, were collected.

Results

Fourteen patients with X chromosome abnormality were included, among which 13 patients underwent a total of 29 cycles. Patients in Group B had five successful pregnancies and three live births, while no patient in Group A had a clinical pregnancy. Furthermore, the blastocyst formation rate and incidence of pregnancy were significantly lower in Group A (Z = −3.135, p = .002; Z = −2.946, p = .003, respectively). When controlled covariates, the karyotype of one normal X was also a risk factor for both blastocyst formation rate and success pregnancy (β = .820, 95% confidence interval [CI] = 0.458–1.116, β = .333, 95% CI = 0.017–0.494, respectively).

Conclusions

Our results revealed that women with only one normal X might suffer from worse IVF outcomes, mainly blastocyst formation rate, compared with those who had two or more normal X, including mosaic Turner syndrome and 47,XXX.

背景：描述并总结X染色体异常患者的体外受精（IVF）结果：描述并总结 X 染色体异常患者的体外受精（IVF）结果：方法：进行了一项回顾性病例系列研究。根据正常 X 的数量，将患者分为两组：A组（只有一条X染色体正常，其他X染色体有任何类型异常的患者）和B组（有两条或两条以上X染色体正常的患者）。收集临床数据，包括基本信息、生育信息和试管婴儿结果：结果：共纳入了 14 名 X 染色体异常患者，其中 13 名患者共接受了 29 个周期的治疗。B 组患者成功妊娠 5 例，活产 3 例，而 A 组患者没有临床妊娠。此外，A 组的囊胚形成率和妊娠发生率明显较低（Z = -3.135，p = .002；Z = -2.946，p = .003）。当控制协变量时，一个正常 X 的核型也是囊胚形成率和成功妊娠率的风险因素（β = .820，95% 置信区间 [CI] = 0.458-1.116；β = .333，95% CI = 0.017-0.494）：我们的研究结果表明，与有两个或两个以上正常 X（包括特纳综合征镶嵌型和 47,XXX 型）的妇女相比，只有一个正常 X 的妇女的试管婴儿结果（主要是囊胚形成率）可能更差。

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引用次数: 0

Prenatal diagnosis of fetuses with absent/hypoplastic nasal bone in second-trimester using chromosomal microarray analysis 利用染色体微阵列分析对第二孕期鼻骨缺失/发育不良的胎儿进行产前诊断。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-20 DOI: 10.1002/bdr2.2351

Xinying Chen, Yuying Jiang, Shuhong Zeng, Jianlong Zhuang, Na Lin

Background

Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype–phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA.

Methods

Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non-isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses.

Results

Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non-isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p < .05).

Conclusion

The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA.

背景：致病性拷贝数变异（pCNVs）与胎儿超声异常有关，可通过染色体微阵列分析（CMA）有效识别。本研究的主要目的是利用 CMA 进一步了解鼻骨缺失或鼻骨发育不良胎儿的基因型与表型之间的相关性：本研究共纳入 94 例鼻骨缺失/鼻骨发育不良的胎儿，分为孤立性鼻骨缺失/鼻骨发育不良组（49 例）和非孤立性鼻骨缺失/鼻骨发育不良组（45 例）。所有参与研究的孕妇都接受了核型分析和 CMA，以评估胎儿的染色体异常：结果：所有病例均成功进行了核型分析和 CMA 检测。结果：所有病例均成功进行了核型分析和 CMA 检测。核型分析和 CMA 检测结果显示，11 例胎儿存在染色体非整倍体，其中以 21 三体综合征最为常见。核型分析检测到的一条小的超常标记染色体（sSMC）被 CMA 进一步解释为 pCNV。此外，尽管核型分析结果正常，但 CMA 检测仍发现了三例 pCNV。其中一例罗氏易位被鉴定为 15 号染色体上的 UPD，15 三体比例较低。此外，非分离型和分离型缺失/增生性鼻骨的 pCNVs 检出率有明显差异（24.44% vs. 8.16%，p 结论：本研究提高了 pCNVs 检测的实用性：本研究提高了 CMA 在诊断胎儿鼻骨缺失或鼻骨发育不良病因方面的实用性。此外，孤立的鼻骨缺失或鼻骨发育不良病例强烈提示存在染色体异常，因此有必要通过 CMA 进行遗传学评估。

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引用次数: 0

Radiosensitivity in a newborn with microcephalia: A case report of Nijmegen breakage syndrome 患有小耳症的新生儿的辐射敏感性：奈梅亨断裂综合征病例报告。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-18 DOI: 10.1002/bdr2.2346

Gunes Cakmak Genc, Busra Yilmaz, Sevim Karakas Celik, Cumhur Aydemir, Recep Eroz, Ahmet Dursun

Aim

Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder which is characterized by immunodeficiency and increased risk of lymphoproliferative malignancy.

Case

We observed an increase in the rate of chromosomal rearrangements in the cultured cells following an incidental radiograph for craniosynostosis in a newborn who was followed up due to microcephaly. We identified a homozygous deletion of c.657_661delACAAA/p.Lys219fs (rs587776650) in the NBN gene through whole exome sequencing.

Conclusion

It is crucial to thoroughly examine the clinical features of newborns with microcephaly and consider chromosomal instability syndromes just like Nijmegen breakage syndrome. Not overlooking radiosensitivity, which is a characteristic feature of this syndrome, is a vital condition to the patient's survival time.

目的：奈梅亨断裂综合征（NBS）是一种常染色体隐性遗传 DNA 修复障碍，其特征是免疫缺陷和淋巴增生性恶性肿瘤风险增加：我们观察到，一名因小头畸形而接受随访的新生儿，在一次偶然的颅骨发育不良放射影像检查后，其培养细胞的染色体重排率增加。我们通过全外显子测序确定了 NBN 基因中 c.657_661delACAAA/p.Lys219fs (rs587776650) 的同源缺失：结论：彻底检查小头畸形新生儿的临床特征并考虑染色体不稳定综合征（如奈梅亨断裂综合征）至关重要。不要忽视辐射敏感性这一综合征的特征，这对患者的存活时间至关重要。

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引用次数: 0

(−)-Epicatechin gallate ameliorates cyprodinil-induced cardiac developmental defects through inhibiting aryl hydrocarbon receptor in zebrafish (-)-表儿茶素没食子酸酯通过抑制斑马鱼体内的芳基烃受体改善环丁胺诱导的心脏发育缺陷

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-18 DOI: 10.1002/bdr2.2350

Dongqin Huang, Yuchao Su, Mingmei Li, Chengwei Xie, Weibin Hu, Shuxiang Wang, Nanmei Zheng, Jianhui Chen, Yueyun Lin, Weize Cai, Jianjia Xiao, Baojia Chen, Nanping Hu, Fushan Zhou

Background

Cyprodinil is a widely used fungicide with broad-spectrum activity, but it has been associated with cardiac abnormalities. (−)-Epicatechin gallate (ECG), a natural polyphenolic compound, has been shown to possess protective properties in cardiac development.

Methods

In this study, we investigated whether ECG could mitigate cyprodinil-induced heart defects using zebrafish embryos as a model. Zebrafish embryos were exposed to cyprodinil with or without ECG.

Results

Our results demonstrated that ECG significantly improved the survival rate, embryo movement, and hatching delay induced by cyprodinil. Furthermore, ECG effectively ameliorated cyprodinil-induced cardiac developmental toxicity, including pericardial anomaly and impairment of cardiac function. Mechanistically, ECG attenuated the cyprodinil-induced alterations in mRNA expression related to cardiac development, such as amhc, vmhc, tbx5, and gata4, as well as calcium ion channels, such as ncx1h, atp2a2a, and cdh2. Additionally, ECG was found to inhibit the activity of the aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil.

Conclusions

In conclusion, our findings provide evidence for the protective effects of ECG against cyprodinil-induced cardiac developmental toxicity, mediated through the inhibition of AhR activity. These findings contribute to a better understanding of the regulatory mechanisms and safe utilization of pesticide, such as cyprodinil.

背景：嘧菌酯是一种广泛使用的杀真菌剂，具有广谱活性，但它与心脏异常有关。(-)-表儿茶素没食子酸酯（ECG）是一种天然多酚化合物，已被证明对心脏发育具有保护作用：在这项研究中，我们以斑马鱼胚胎为模型，研究了表儿茶素是否能减轻环丙地尼所诱发的心脏缺陷。将斑马鱼胚胎暴露于含或不含心电图的环丙地尼中：结果：我们的研究结果表明，心电图能明显改善环丙地尼诱导的斑马鱼胚胎存活率、胚胎运动和孵化延迟。此外，心电图还能有效改善环丙地尼诱导的心脏发育毒性，包括心包畸形和心脏功能损害。从机理上讲，ECG可减轻环丙地尼诱导的与心脏发育有关的mRNA表达变化，如amhc、vmhc、tbx5和gata4，以及钙离子通道，如ncx1h、atp2a2a和cdh2。此外，还发现心电图抑制了环丙地尼诱导的芳基烃受体（AhR）信号通路的活性：总之，我们的研究结果为心电图通过抑制 AhR 活性对环丙地尼诱导的心脏发育毒性的保护作用提供了证据。这些研究结果有助于更好地理解农药（如环丙地尼）的调控机制和安全使用。

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引用次数: 0

Association of MTHFR (C677T, A1298C) and MTRR A66G polymorphisms with fatty acids profile and risk of neural tube defects MTHFR（C677T、A1298C）和 MTRR A66G 多态性与脂肪酸谱和神经管畸形风险的关系。

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-08 DOI: 10.1002/bdr2.2333

Kaouther Nasri, Nadia Ben Jamaa, Soumeya Siala Gaigi, Moncef Feki, Raja Marrakchi

Objective

This study aims to determine if 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms were associated with fatty acid (FA) levels in mothers of fetuses with neural tube defects (NTDs) and whether these associations were modified by environmental factors.

Methods

Plasma FA composition was assessed using capillary gas chromatography. Concentrations of studied FA were compared between 42 mothers of NTDs fetuses and 30 controls as a function of each polymorphism by the Kruskal–Wallis nonparametric test.

Results

In MTHFR gene C677T polymorphism, cases with (CT + TT) genotype had lower monounsaturated FAs (MUFA) and omega-3 polyunsaturated FA (n-3 PUFA) levels, but higher omega-6 polyunsaturated FAs (n-6 PUFA) and omega-6 polyunsaturated FAs: omega-3 polyunsaturated FAs (n-6:n-3) ratio levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype had lower MUFA levels, but higher PUFA and n-6 PUFA levels. Controls with (AG + GG) genotype had lower n-6 PUFA levels. In MTHFR gene C677T polymorphism, cases with smoking spouses and (CT + TT) genotype had lower MUFA and n-3 PUFA levels, but higher PUFA, n-6 PUFA, and n-6:n-3 ratio levels. Cases with (CT + TT) genotype and who used sauna during pregnancy had lower n-3 PUFA levels. In MTRR gene A66G polymorphism, cases with (AG + GG) genotype and who used sauna during pregnancy had higher PUFA and n-6 PUFA levels.

Conclusions

Further research is required to clarify the association of FA metabolism and (MTHFR, MTRR) polymorphisms with NTDs.

研究目的本研究旨在确定5,10-亚甲基四氢叶酸还原酶（MTHFR C677T和A1298C）和蛋氨酸合成酶还原酶（MTRR A66G）基因多态性是否与神经管缺陷（NTD）胎儿母亲体内的脂肪酸（FA）水平有关，以及这些关联是否会因环境因素而改变：方法：使用毛细管气相色谱法评估血浆中的脂肪酸组成。通过 Kruskal-Wallis 非参数检验，比较了 42 位 NTD 胎儿母亲和 30 位对照组之间所研究的 FA 浓度与每种多态性的关系：结果：在MTHFR基因C677T多态性中，基因型为（CT + TT）的病例的单不饱和脂肪酸（MUFA）和ω-3多不饱和脂肪酸（n-3 PUFA）水平较低，但ω-6多不饱和脂肪酸（n-6 PUFA）和ω-6多不饱和脂肪酸：ω-3多不饱和脂肪酸（n-6:n-3）比率水平较高。在 MTRR 基因 A66G 多态性中，基因型为（AG + GG）的病例的 MUFA 含量较低，但 PUFA 和 n-6 PUFA 含量较高。基因型为（AG + GG）的对照组 n-6 PUFA 含量较低。在 MTHFR 基因 C677T 多态性方面，配偶吸烟且基因型为（CT + TT）的病例的 MUFA 和 n-3 PUFA 水平较低，但 PUFA、n-6 PUFA 和 n-6:n-3 比率水平较高。基因型为（CT + TT）且在孕期使用桑拿浴的病例的 n-3 PUFA 水平较低。在 MTRR 基因 A66G 多态性中，基因型为（AG + GG）且在孕期使用桑拿浴的病例的 PUFA 和 n-6 PUFA 水平较高：需要进一步研究以明确脂肪酸代谢和（MTHFR、MTRR）多态性与 NTD 的关系。

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引用次数: 0

Reversible effects on female rat fertility with abrocitinib, a Janus kinase 1 inhibitor Janus 激酶 1 抑制剂阿罗西替尼对雌鼠生育能力的可逆影响

IF 2.1 4区医学 Q4 DEVELOPMENTAL BIOLOGY

Birth Defects Research

Pub Date : 2024-05-08 DOI: 10.1002/bdr2.2345

Christopher J. Bowman, Sarah N. Campion, Natasha R. Catlin, William S. Nowland, Christine M. Stethem, Zaher A. Radi, Gregg D. Cappon

Background

Abrocitinib is a Janus kinase (JAK) 1 selective inhibitor approved for the treatment of atopic dermatitis. Female reproductive tissues were unaffected in general toxicity studies, but an initial female rat fertility study resulted in adverse effects at all doses evaluated. A second rat fertility study was conducted to evaluate lower doses and potential for recovery.

Methods

This second study had 4 groups of 20 females each administered abrocitinib (0, 3, 10, or 70 mg/kg/day) 2 weeks prior to cohabitation through gestation day (GD) 7. In addition, 2 groups of 20 rats (0 or 70 mg/kg/day) were dosed for 3 weeks followed by a 4-week recovery period before mating. All mated females were evaluated on GD 14.

Results

No effects were observed at ≤10 mg/kg/day. At 70 mg/kg/day (29x human exposure), decreased pregnancy rate, implantation sites, and viable embryos were observed. All these effects reversed 4 weeks after the last dose.

Conclusions

Based on these data and literature on the potential role of JAK signaling in implantation, we hypothesize that these effects may be related to JAK1 inhibition and, generally, that peri-implantation effects such as these, in the absence of cycling or microscopic changes in nonpregnant female reproductive tissues, are anticipated to be reversible.

背景介绍阿罗西替尼是一种 Janus 激酶 (JAK) 1 选择性抑制剂，已被批准用于治疗特应性皮炎。在一般毒性研究中，雌性生殖组织未受影响，但在最初的雌性大鼠生育力研究中，在所有评估剂量下都出现了不良反应。我们进行了第二次大鼠生育力研究，以评估较低剂量和恢复的可能性：在第二次研究中，4 组 20 只雌性大鼠在同居前 2 周至妊娠第 7 天分别服用阿罗西替尼（0、3、10 或 70 毫克/千克/天）。此外，2 组 20 只大鼠（0 或 70 毫克/千克/天）连续用药 3 周，然后在交配前经过 4 周的恢复期。所有交配的雌性大鼠均在广东十一选五期第 14 天接受评估：结果：当剂量≤10 毫克/千克/天时，未观察到任何影响。当剂量为 70 毫克/千克/天（人体接触量的 29 倍）时，妊娠率、着床部位和存活胚胎均有所下降。最后一次用药 4 周后，所有这些影响都会逆转：根据这些数据以及有关 JAK 信号在植入过程中的潜在作用的文献，我们推测这些影响可能与 JAK1 抑制有关，而且一般来说，在非妊娠女性生殖组织没有发生周期性或微观变化的情况下，这些植入周围影响预计是可逆的。

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