Nitrofen
(Synonyms: 护谷) 目录号 : GC44407
A teratogenic herbicide used to model CDH
Cas No.:1836-75-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Nitrofen is an herbicide with potent teratogenic activity in rats and mice. It induces bilateral pulmonary hypoplasia and an immature lung architecture in fetal rats and mice, which is used to model human congenital diaphragmatic hernia.
| Cas No. | 1836-75-5 | SDF | |
| 别名 | 护谷 | ||
| Canonical SMILES | ClC1=C(OC2=CC=C([N+]([O-])=O)C=C2)C=CC(Cl)=C1 | ||
| 分子式 | C12H7Cl2NO3 | 分子量 | 284.1 |
| 溶解度 | Methanol: Soluble | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.5199 mL | 17.5994 mL | 35.1989 mL |
| 5 mM | 0.704 mL | 3.5199 mL | 7.0398 mL |
| 10 mM | 0.352 mL | 1.7599 mL | 3.5199 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Nitrofen: a review and perspective
Toxicology 1983 Dec;29(1-2):1-37.PMID:6362073DOI:10.1016/0300-483x(83)90036-7.
With the exception of occasional reports of skin irritation, 20 years of commercial Nitrofen use has not produced indications of toxicity in man. In mature non-pregnant laboratory animals Nitrofen is only slightly toxic after acute oral, dermal, or respiratory exposures, and it is not a sensitizer. However, absorption through skin occurs rapidly from solvent-based formulations. Chronic administration in the diet at doses of 20 mg/kg body wt/day and higher produced liver toxicity in mice, rats, and dogs with liver tumors developing in mice at dose levels at 470 mg/kg/day. In addition to liver tumors in mice, the National Cancer Institute's Carcinogen Bioassay Program also found a dose-related incidence of pancreatic tumors in females of 1 of 2 strains of rat after lifetime feeding at levels at and above 65 mg/kg/day. Single and repeated doses given during pregnancy to rats and mice produce neonatal lethality accompanied by signs of impaired breathing, diaphragmatic hernias, heart anomalies, hydronephrosis, and apparent eye anomalies which are due to effects on the Harderian gland. These anomalies were produced by both oral and dermal doses, but did not occur in the rabbit or when dosing was restricted to the male parent only. Neonatal deaths appear after repeated maternal doses of 3 mg/kg/day and higher; the overall no observed effect level for effects in the offspring was 0.17 mg/kg/day. Based on a 10(-6) level of tumorigenic risk the acceptable average daily intake for man is 1 microgram/kg/day; pregnant women should not be exposed to more than 1.7 micrograms/kg in any single 24-h period.
Yes-associated protein is dysregulated during nitrofen-induced hypoplastic lung development due to congenital diaphragmatic hernia
Pediatr Surg Int 2022 May;38(5):713-719.PMID:35226175DOI:10.1007/s00383-022-05099-x.
Background: Congenital diaphragmatic hernia (CDH) is a birth defect associated with abnormal lung development. Yes-associated protein (YAP) is a core kinase of the Hippo pathway, which controls organ size during development. The absence of YAP protein during lung development results in hypoplastic lungs comparable to the lung phenotype in CDH (Mahoney, Dev Cell 30(2):137-150, 2014). We aimed to describe the expression of YAP during normal and nitrofen-induced abnormal lung development. Methods: Intra-gastric administration of dams with 100 mg of Nitrofen was used to induce CDH and abnormal lung development in the embryos. Immunofluorescence was performed to visualize the localization of YAP and p-YAP during lung development (E15, E18, E21). Western Blotting was used to determine the abundance of YAP and p-YAP in E21 control and nitrofen-induced hypoplastic CDH lungs. Results: Immunofluorescence demonstrated cytoplasmic localization of YAP protein in airway epithelial and mesenchymal cells of nitrofen-induced hypoplastic lungs compared to nuclear localization in control lungs. Western Blotting showed a decrease (p = 0.0188) in abundance of YAP (active form) and increase in p-YAP (inactive form) in hypoplastic lungs compared to control lungs. Conclusion: Our results demonstrate that YAP protein is mostly phosphorylated, inactive, and expressed in the cytoplasm at the later stages of nitrofen-induced hypoplastic lung development indicating that the alteration in regulation of YAP can be associated with the pathogenesis of abnormal lung development in experimental CDH.
Extracellular Vesicles Attenuate Nitrofen-Mediated Human Pulmonary Artery Endothelial Dysfunction: Implications for Congenital Diaphragmatic Hernia
Stem Cells Dev 2020 Aug 1;29(15):967-980.PMID:32475301DOI:10.1089/scd.2020.0063.
Congenital diaphragmatic hernia (CDH) leads to pathophysiologic pulmonary vasoreactivity. Previous studies show that mesenchymal stromal cell-derived extracellular vesicles (MSCEv) inhibit lung inflammation and vascular remodeling. We characterize MSCEv and human pulmonary artery endothelial cell (HPAEC) interaction, as well as the pulmonary artery (PA) response to MSCEv treatment. HPAECs were cultured with and without exposure to Nitrofen (2,4-dichloro-phenyl-p-nitrophenylether) and treated with MSCEv. HPAEC viability, architecture, production of reactive oxygen species (ROS), endothelial dysfunction-associated protein levels (PPARγ, LOX-1, LOX-2, nuclear factor-κB [NF-κB], endothelial NO synthase [eNOS], ET-1 [endothelin 1]), and the nature of MSCEv-cellular interaction were assessed. Newborn rodents with and without CDH (Nitrofen model and Sprague-Dawley) were treated with intravascular MSCEv or vehicle control, and their PAs were isolated. Contractility was assessed by wire myography. The contractile (KCL and ET-1) and relaxation (fasudil) responses were evaluated. HPAEC viability correlated inversely with Nitrofen dose, while architectural compromise was directly proportional. There was a 2.1 × increase in ROS levels in Nitrofen HPAECs (P < 0.001), and MSCEv treatment attenuated ROS levels by 1.5 × versus Nitrofen HPAECs (P < 0.01). Nitrofen-induced alterations in endothelial dysfunction-associated proteins are shown, and exposure to MSCEv restored more physiologic expression. Nitrofen HPAEC displayed greater MSCEv uptake (80% increase, P < 0.05). Adenosine, a clathrin-mediated endocytosis inhibitor, decreased uptake by 46% (P < 0.05). CDH PA contraction was impaired with KCL (108.6% ± 1.4% vs. 112.0% ± 1.4%, P = 0.092) and ET-1 (121.7% ± 3.0% vs. 131.2% ± 1.8%, P < 0.01). CDH PA relaxation was impaired with fasudil (32.2% ± 1.9% vs. 42.1% ± 2.2%, P < 0.001). After MSCEv treatment, CDH PA contraction improved (125.9% ± 3.4% vs. 116.4 ± 3.5, P = 0.06), and relaxation was unchanged (32.5% ± 3.2% vs. 29.4% ± 3.1%, P = 0.496). HPAEC exposure to Nitrofen led to changes consistent with vasculopathy in CDH, and MSCEv treatment led to a more physiologic cellular response. MSCEv were preferentially taken up by nitrofen-treated cells by clathrin-dependent endocytosis. In vivo, MSCEv exposure improved PA contractile response. These data reveal mechanisms of cellular and signaling alterations that characterize MSCEv-mediated attenuation of pulmonary vascular dysfunction in CDH-associated pulmonary hypertension.
Recent advances in understanding the pathogenesis of nitrofen-induced congenital diaphragmatic hernia
Pediatr Pulmonol 2000 May;29(5):394-9.PMID:10790252DOI:10.1002/(sici)1099-0496(200005)29:5<394::aid-ppul9>3.0.co;2-2.
In this review, we discuss recent advances in the study of the pathogenesis of congenital diaphragmatic hernia (CDH). Much of the research has involved the use of an animal model of CDH in which diaphragmatic defects are produced in fetal rats by administering the herbicide Nitrofen to dams during mid-gestation. The animal model is described and the relevance to the human condition is discussed. The data derived from the animal studies are critically assessed in the context of commonly cited hypotheses proposed for the pathogenesis of CDH. Finally, experimental strategies are proposed for systematically examining the normal and pathological formation of the pleuroperitoneal fold. We conclude that a malformation of the primordial diaphragm, the pleuroperitoneal fold, underlies the muscle defects associated with CDH.
Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition
Birth Defects Res B Dev Reprod Toxicol 2010 Jun;89(3):223-32.PMID:20549697DOI:10.1002/bdrb.20247.
Background: Nitrofen is a diphenyl ether that induces congenital diaphragmatic hernia (CDH) in rodents. Its mechanism of action has been hypothesized as inhibition of the retinaldehyde dehydrogenase (RALDH) enzymes with consequent reduced retinoic acid signaling. Methods: To determine if Nitrofen inhibits RALDH enzymes, a reporter gene construct containing a retinoic acid response-element (RARE) was transfected into HEK-293 cells and treated with varying concentrations of Nitrofen in the presence of retinaldehyde (retinal). Cell death was characterized by caspace-cleavage microplate assays and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays. Ex vivo analyses of cell viability were characterized in fetal rat lung explants using Live/Dead staining. Cell proliferation and apoptosis were assessed using fluorescent immunohistochemistry with phosphorylated histone and activated caspase antibodies on explant tissues. Nile red staining was used to identify intracellular lipid droplets. Results: Nitrofen-induced dose-dependent declines in RARE-reporter gene expression. However, similar reductions were observed in control-reporter constructs suggesting that Nitrofen compromised cell viability. These observed declines in cell viability resulted from increased cell death and were confirmed using two independent assays. Ex vivo analyses showed that mesenchymal cells were particularly susceptible to nitrofen-induced apoptosis while epithelial cell proliferation was dramatically reduced in fetal rat lung explants. Nitrofen treatment of these explants also showed profound lipid redistribution, primarily to phagocytes. Conclusions: The observed declines in nitrofen-associated retinoic acid signaling appear to be independent of RALDH inhibition and likely result from Nitrofen induced cell death/apoptosis. These results support a cellular apoptotic mechanism of CDH development, independent of RALDH inhibition.