Effects of antioxidant vitamins on molecular regulators involved in lung hypoplasia induced by nitrofen.
BACKGROUND
Oxidant herbicide nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) induces in rat embryos congenital diaphragmatic hernia (CDH) with lung hypoplasia. The present study aims at examining whether antioxidant vitamins A, E, and C reverse the effects of the teratogen in the lungs of exposed rats and how they modify the expression of molecular regulators known to be involved in their pathogenesis.


METHODS
Wet lung weight-body weight ratio, total DNA, and total protein were determined. Thyroid transcription factor 1 (TTF-1), hepatocyte nuclear factor 3beta (HNF-3beta), and surfactant protein B (SP-B) proteins were measured by immunoblot assay in lung homogenates from rat fetuses exposed in utero to either nitrofen 100 mg intragastrically or vehicle. The coexpression of these factors in the alveolar epithelium was demonstrated by immunohistochemistry. The effects of the addition of vitamins A, C, and E were assessed by comparison with analysis of variance.


RESULTS
Nitrofen decreased lung weight, total DNA, and total protein. The addition of antioxidant vitamins had no effect on lung weight, but increased DNA and protein contents. TTF-1, HNF-3beta, and SP-B proteins were decreased in lung homogenates of exposed rats with CDH. The addition of antioxidant vitamins nearly normalized these values.


CONCLUSIONS
The effects of nitrofen in fetal rat lungs are reversed in part by antioxidant vitamins by upregulating the expression of TTF-1, HNF-3beta, and SP-B. This approach could help to develop transplacental prenatal interventions for CDH.
Gonzalez-Reyes
Salome
S
Department of Pediatric Surgery, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain.
Martinez
Leopoldo
L
Martinez-Calonge
Wenceslao
W
Fernandez-Dumont
Virginia
V
Tovar
Juan A
JA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D005260:Female; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis; D006540:Herbicides / Q000009:adverse effects*; D006548:Hernia, Diaphragmatic / Q000150:complications; D008168:Lung / Q000002:abnormalities / Q000187:drug effects* / Q000601:surgery; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009687:Nuclear Proteins / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis; D010647:Phenyl Ethers / Q000009:adverse effects*; D011247:Pregnancy; D011510:Proteolipids / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015619:Respiratory System Abnormalities; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D014801:Vitamin A / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology*
D000975:Antioxidants; D006540:Herbicides; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010647:Phenyl Ethers; D011510:Proteolipids; C088514:SP-B protein (53-78); D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D014815:Vitamins; D014801:Vitamin A; D051542:Hepatocyte Nuclear Factor 3-beta; D014810:Vitamin E; C007350:nitrofen; D001205:Ascorbic Acid