Toxicologic studies on 2,4-dichlorophenyl-p-nitrophenyl ether

Ambrose, Anthony M.; Larson, Paul; Borzelleca, Joseph F.; Smith, Robert B.; Hennigar, Gordon R.

doi:10.1016/0041-008x(71)90111-6

Cited by 92 publications

(30 citation statements)

References 4 publications

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“…3,4 Diaphragmatic defects resulting from a single 100-mg dose of nitrofen administered to pregnant rats on day 8 of gestation are very similar to those documented in human CDH, with respect to the size and location of the defect and the accompanying intrusion of the abdominal viscera into the thoracic cavity. Further, the associated developmental defects observed with nitrofen-induced CDH such as skeletal and cardiac malformations are similar to those seen in a subpopulation of infants with CDH.…”

Section: 2supporting

confidence: 49%

Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Mey¹,

Babiuk

Clugston

et al. 2003

The American Journal of Pathology

123

127

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Currently, the etiology of the serious developmental anomaly congenital diaphragmatic hernia (CDH) is unknown. We have used an animal model of CDH to address this issue. We characterized four separate teratogens that produced diaphragmatic defects in embryonic rats that are similar to those in infants with CDH. We then tested the hypothesis that all these agents share the common mechanism of perturbing the retinoid-signaling pathway. Specifically, inhibition of retinal dehydrogenase-2 (RALDH2), a key enzyme necessary for the production of retinoic acid and that is expressed in the developing diaphragm, was assayed by measuring retinoic acid production in cytosolic extracts from an oligodendrocyte cell line. The following compounds all induce posterolateral defects in the rat diaphragm; nitrofen, 4-biphenyl carboxylic acid, bisdiamine, and SB-210661. Importantly, we demonstrate that they all share the common mechanism of inhibiting RALDH2. These data provide an important component of mounting evidence suggesting that the retinoid system warrants consideration in future studies of the etiology of CDH. Congenital diaphragmatic hernia (CDH) is a serious developmental disorder occurring in ϳ1 in 3000 live births in which the diaphragm muscle fails to form completely, resulting in a hole in the diaphragm and incomplete separation of the thoracic and abdominal cavities. Lung hypoplasia and pulmonary hypertension are major pathological consequences that account for much of the morbidity and mortality of this problem.

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Section: 2supporting

confidence: 49%

Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Mey¹,

Babiuk

Clugston

et al. 2003

The American Journal of Pathology

123

127

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“…Originally, nitrofen (2,4-dichlorophenyl-p -nitrophenyl ether) was used as a herbicide. In toxicology screens in adult rats, no apparent problems were observed, though administration during midgestation to pregnant dams appeared to cause developmental anomalies of the heart, lungs, diaphragm, and skeleton of the embryos [49,50] . Based on the latter findings, nitrofen has been investigated for its usefulness to simulate the anomalies of CDH in rodents.…”

Section: Nitrofen Modelmentioning

confidence: 99%

Congenital Diaphragmatic Hernia: Comparison of Animal Models and Relevance to the Human Situation

et al. 2009

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Congenital diaphragmatic hernia (CDH) occurs in 1 in 3,000 newborns. Mortality and morbidity are due to the amount of pulmonary hypoplasia (PH), the response on artificial ventilation and the presence of therapy-resistant pulmonary hypertension. The pathogenesis and etiology of CDH and its associated anomalies are still largely unknown despite all research efforts over the past years. Several animal models have been proposed to study CDH. In this review we compare surgical, pharmacological and transgenic models, and discuss their strengths and limitations to study PH.

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“…During the past two decades, a well-established model to study CDH in rodents has been developed through the use of the herbicide nitrofen (2,4-dichloro-p-nitrophenyl ether) (14,28,35,50). When a maternal rat or mouse is fed nitrofen at precise time points of lung embryogenesis (E9.5 in rats, E8.5 in mice), the fetus often develops features of CDH that include bilateral lung hypoplasia, with more severe changes on the left lung, and in many cases, diaphragmatic defects (6,14,23,25,35,50). Nitrofen exposure induces small lungs with reduced airway branching and septation, thickened interstitium, and reduced vascular density (10,35).…”

mentioning

confidence: 99%

Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants

Muehlethaler

Kunig²,

Seedorf³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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We hypothesized that abnormal fetal lung growth in experimental congenital diaphragmatic hernia after maternal nitrofen exposure alters lung structure due to impaired VEGF signaling, which can be reversed with VEGF or nitric oxide (NO) treatment. Timed-pregnant Sprague-Dawley rats were treated with nitrofen on embryonic day 9 (E9), and fetal lungs were harvested for explant culture on E15. Explants were maintained in 3% O2for 3 days and were treated with NO gas or recombinant human VEGF protein for 3 days. To determine the effects of VEGF inhibition on lung structure, normal fetal lung explants were treated with SU-5416, a VEGF receptor inhibitor, with or without exogenous NO or VEGF. We found that nitrofen treatment impaired lung structure, as evidenced by decreased branching at day 0, but lung structure was not different from controls after 3 days in culture. Nitrofen reduced lung VEGF but not endothelial NO synthase protein level. Treatment with NO enhanced lung growth in control and nitrofen-exposed lungs; however, the response to NO in the nitrofen-treated lungs was reduced when compared with controls. VEGF treatment did not cause a further increase in lung complexity after nitrofen exposure. SU-5416 treatment altered lung structure, which improved with NO but not VEGF treatment. Both nitrofen and SU-5416 treatment increased apoptosis in the mesenchyme of fetal lung explants. We conclude that nitrofen exposure increased apoptosis, decreased lung growth and reduced VEGF expression, and that exogenous NO but not VEGF treatment enhances lung growth. Disruption of lung architecture after VEGF receptor blockade was similar to nitrofen-induced changes but was more responsive to NO.

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Toxicologic studies on 2,4-dichlorophenyl-p-nitrophenyl ether

Cited by 92 publications

References 4 publications

Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Congenital Diaphragmatic Hernia: Comparison of Animal Models and Relevance to the Human Situation

Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants

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