Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Solomon, Howard M.; Wier, Patrick J.; Johnson, Connie; Posobiec, Lorraine M.; Rendemonti, Joyce; Rumberger, Douglas

doi:10.1002/(sici)1096-9926(200003)61:3<211::aid-tera9>3.0.co;2-e

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…The cardiac defects may result from problems with neural crest proliferation and differentiation in the fetuses. 14,15,17,25,26 There is no strong evidence, however, that diaphragm embryogenesis has any dependence on neural crest development. It may be that these compounds also interfere with the proliferation or differentiation of mesenchymal cells.…”

Section: Discussionmentioning

confidence: 94%

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

122

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: Discussionmentioning

confidence: 94%

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

122

127

View full text Add to dashboard Cite

show abstract

“…Multiple teratogens have been described that induce CDH in rodent models [Kimmel et al, 1971; Barr, 1973; Taleporos et al, 1978; Manson, 1986; Sutherland et al, 1989; Solomon et al, 2000; Cappon et al, 2003; Gupta et al, 2003]. Among these compounds, nitrofen is the best characterized and will be discussed initially followed by a discussion of other known agents.…”

Section: Teratogenic Modelsmentioning

confidence: 99%

“…Table IV shows several compounds affecting inflammatory processes, which have been associated with CDH, plus additional malformations, in rodent models. Both the SB‐202235 and SB‐210661 are benzofuranyl urea derivatives that inhibit 5‐lipoxygenase (5‐LOX), blocking the metabolism of arachidonic acid to leukotrienes and hydroxyeicosatetrenoic acids [Solomon et al, 2000]. Although both SB‐210661 and SB‐202235 were shown to induce CDH, SB210661 was shown to be a more potent inducer of defects [Solomon et al, 2000].…”

Section: Teratogenic Modelsmentioning

confidence: 99%

Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH)

Kling

Schnitzer

2007

American J of Med Genetics Pt C

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Congenital diaphragmatic hernia (CDH) is a congenital malformation that occurs with a frequency of 0.08 to 0.45 per 1,000 births. Children with CDH are born with the abdominal contents herniated through the diaphragm and exhibit an associated pulmonary hypoplasia which is frequently accompanied by severe morbidity and mortality. Although the etiology of CDH is largely unknown, considerable progress has been made in understanding its molecular mechanisms through the usage of genetic, teratogenic, and surgical models. The following review focuses on the teratogenic and surgical models of CDH and the possible molecular mechanisms of nitrofen (a diphenyl ether, formerly used as an herbicide) in both induction of CDH and pulmonary hypoplasia. In addition, the mechanisms of other compounds including several anti-inflammatory agents that have been linked to CDH will be discussed. Furthermore, this review will also explore the importance of vitamin A in lung and diaphragm development and the possible mechanisms of teratogen interference in vitamin A homeostasis. Continued exploration of these models will bring forth a clearer understanding of CDH and its molecular underpinnings, which will ultimately facilitate development of therapeutic strategies.

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“…Other studies have shown that redox phenomena might be involved in the mechanism of action of nitrofen [13]. Finally, other teratogens capable of inducing CDH and the whole spectrum of associated malformations in rat fetuses, such as bis-diamine [26], SB-210661 [27], and 4-biphenyl carboxylic acid [28], are oxidant agents.…”

Section: Discussionmentioning

confidence: 99%

Effects of antioxidant vitamins on molecular regulators involved in lung hypoplasia induced by nitrofen

González-Reyes¹,

Martínez²,

Martínez-Calonge³

et al. 2006

Journal of Pediatric Surgery

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Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Cited by 8 publications

References 40 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

Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH)

Effects of antioxidant vitamins on molecular regulators involved in lung hypoplasia induced by nitrofen

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