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Bertrand Rihn,¹ Catherine Coulais,¹ Edmond Kauffer,¹ Marie-Claire Bottin,¹ Patrick Martin,¹ Francois Yvon,¹ Jean Claude Vigneron,¹ Stéphane Binet,¹ Nathalie Monhoven,² Guy Steiblen,³ and Gérard Keith³

¹Institut National de Recherche et de Sécurité, Vandoeuvre, France
²Laboratoire de Biologie Moléculaire de l'Hôpital Central de Nancy, Nancy, France
³Unité Propre de Recherche 9002 du CNRS, Strasbourg, France

Abstract

We used transgenic mice carrying the lacI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-only inhalation to an aerosol containing 5.75 mg/m³ crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacI reporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 ± 103 ng/mg lung) . There was evidence of a typical inflammatory response consisting of multinucleate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonuclear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 10^-5 in the exposed group versus 6.9 10^-5 in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the ³²P-postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation. Key words: adduct, asbestos, crocidolite, lung DNA, lacI gene, macrophage, mutation, transgenic. Environ Health Perspect 108:341-346 (2000) . [Online 23 February 2000]

http://ehpnet1.niehs.nih.gov/docs/2000/108p341-346rihn/ abstract.html

Address correspondence to B. Rihn, Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27 54501 Vandoeuvre Cédex, France. Telephone: 33 383 502 062. Fax: 33 383 508 711. E-mail: rihn@inrs.fr

We thank C. Marty, L. Delsaut, M. Villa, and C. Dubon for excellent technical assistance and C. Saliou for critical reading.

This study was partially supported by a grant (SE000482) of the Fondation pour la Recherche Médicale.

Received 27 July 1999 ; accepted 9 November 1999.