Nitrofen-induced diaphragmatic hernias in rats: An animal model

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Abstract

In embryological terms, pathogenesis of congenital diaphragmatic hernia (CDH) associated with pulmonary hypoplasia is still unclear. However, it is known since 1971 that Nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) can induce anatomical malformations in rats including diaphragmatic hernias. On order to establish an animal model of the embryogenesis of CDH, the effect of Nitrofen on the developing diaphragm was studied. Thirty-three pregnant female rats were exposed to Nitrofen. Five unexposed pregnant rats served as controls. In the first set of experiments, single doses of Nitrofen were given between the 9th and 13th day of pregnancy. In the second set of experiments, dosages of 50, 100, and 150 mg per animal were given on day 11 of pregnancy only. Postnatally the litters (469 newborn rats) were dissected to record the incidence of diaphragmatic malformations. The results were: (1) most hernias occurred after administration of 100 mg Nitrofen on day 9 (42%) and 11 (59%); (2) left-sided hernias were observed only after exposure to Nitrofen on day 9; (3) after exposure on day 10 or later all hernias were on the right side; and (4) Fifty-nine percent of the newborn rats exposed on day 11 had CDH. These results show that this model is suitable for further embryological investigations on the development of CDH.

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  • The role of genes and environment in the etiology of congenital diaphragmatic hernias

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    Treatment with BMS493 of rat embryos between E8-E11 leads to CDH (Clugston et al., 2010). Similarly, treatment of pregnant dams with nitrofen or WIN18,446, teratogens that inhibit ALDH1A2 and RA synthesis (Chen et al., 2018; Noble et al., 2007), leads to CDH in mice and rats (Babiuk, Thébaud, & Greer, 2004; Kilburn, Hess, Lesser, & Oster, 1982; Kluth et al., 1990; Momma, Ando, Mori, & Ito, 1992; Rocke et al., 2021; Taleporos, Salgo, & Oster, 1978). Experiments with these pharmacological inhibitors have also provided important mechanistic insights into how defects in RA signaling lead to CDH.

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Presented at the 38th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Chicago, Illinois, October 21–23, 1989.

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