Pharmacodynamics of formaldehyde: applications of a model for the arrest of DNA replication by DNA-protein cross-links.

A variety of evidence suggests that formaldehyde (HCHO)-induced DNA-protein cross-links (DPX) are genotoxic as a result of their ability to arrest DNA replication. Although DPX can be removed and the DNA can be repaired, failure to remove the blockage prior to cell division or excision followed by incomplete repair could cause cell death or a mutation. To characterize the concentration and time dependence of this mechanism, a biologically based model for DNA replication in the presence of DPX was developed based on the assumptions that (1) DPX are formed randomly in the DNA and (2) a replication fork can advance up to but not past a DPX. Using a combination of Poisson and binomial statistics, a quantitative relationship between the amount of newly synthesized DNA and the concentration of DPX was derived, which predicts that the rate of DNA replication should decrease nonlinearly with increasing concentrations of DPX. Because the latter is a nonlinear function of the airborne concentration of HCHO, an inverse sigmoidal relationship is predicted between the rate of DNA replication and the concentration of inhaled formaldehyde. The model was parameterized using data derived from a study of the incorporation of [methyl-(14)C]thymidine monophosphate into the DNA of the nasal respiratory mucosa of Fischer-344 rats exposed to (3)HCHO and H(14)CHO (6 ppm, 6 h). The model was then applied to measurements of DNA replication in the nasal mucosa of experimental animals exposed to wide ranges of H(14)CHO (rats: 0.7, 2, 6, or 15 ppm, 3 h; rhesus monkeys: 0.7, 2, or 6 ppm, 6 h). The results indicate that, at airborne concentrations above 6 ppm in rats, there is a marked decrease (ca. 62% at 15 ppm) in the amount of newly synthesized DNA due to DPX formation during a single 6-h exposure to HCHO. The arrest of DNA replication at high HCHO concentrations could result in cytolethality or genotoxicity, both of which are critical factors in the induction of rat nasal cancer by HCHO. However, at concentrations below 2 ppm in monkeys or 1 ppm in rats, the decrease in the rate of DNA replication is predicted to be <1% after a 6-h exposure. This small decrease is probably undetectable using currently available techniques. The parameterized model suggests that the arrest of DNA replication by DPX is mainly a high-dose phenomenon and that at ambient exposure concentrations it is unlikely to be a major risk factor.

[1]  W. Jencks,et al.  The mechanism of the condensation of formaldehyde with tetrahydrofolic acid. , 1966, The Journal of biological chemistry.

[2]  P. V. von Hippel,et al.  Formaldehyde as a probe of DNA structure. I. Reaction with exocyclic amino groups of DNA bases. , 1975, Biochemistry.

[3]  Stuart L. Meyer,et al.  Data analysis for scientists and engineers , 1975 .

[4]  Gerald D Fasman.  Handbook of Biochemistry , 1976 .

[5]  Y. Morimitsu,et al.  Reaction of formaldehyde with calf-thymus nucleohistone. , 1979, European journal of biochemistry.

[6]  E. Moustacchi,et al.  Biochemical analysis of damage induced in yeast by formaldehyde. , 1980, Mutation research.

[7]  W. Ross,et al.  Relationship between DNA damage and survival in formaldehyde-treated mouse cells. , 1980, Mutation research.

[8]  I. Eto,et al.  Determination of three different pools of reduced one-carbon-substituted folates. III. Reversed-phase high-performance liquid chromatography of the azo dye derivatives of p-aminobenzoylpoly-gamma-glutamates and its application to the study of unlabeled endogenous pteroylpolyglutamates of rat liver. , 1982, Analytical biochemistry.

[9]  A. Place,et al.  Formaldehyde mutagenesis in Drosophila. Molecular analysis of ADH-negative mutants. , 1983, Mutation research.

[10]  A. Natarajan,et al.  Evaluation of the mutagenicity of formaldehyde in mammalian cytogenetic assays in vivo and vitro. , 1983, Mutation research.

[11]  J A Swenberg,et al.  Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. , 1983, Cancer research.

[12]  C. Harris,et al.  Repair of DNA damage caused by formaldehyde in human cells. , 1984, Cancer research.

[13]  T. Starr,et al.  Differentiation between metabolic incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa and bone marrow by inhaled [14C]- and [3H]formaldehyde. , 1984, Toxicology and applied pharmacology.

[14]  M. Solomon,et al.  Formaldehyde-mediated DNA-protein crosslinking: a probe for in vivo chromatin structures. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Haynes.  Molecular mechanisms in genetic stability and change: the role of deoxyribonucleotide pool balance. , 1985, Basic life sciences.

[16]  F. Serres,et al.  Genetic consequences of nucleotide pool imbalance: Edited by F J de Serres. pp 523. plenum press, New York 1985. $69.50 ISBN 0‐306‐41902‐5 , 1986 .

[17]  Schouten Jp.  Hybridization selection of covalent nucleic acid-protein complexes. 2. Cross-linking of proteins to specific Escherichia coli mRNAs and DNA sequences by formaldehyde treatment of intact cells. , 1985 .

[18]  R. Snyder,et al.  Genotoxicity of formaldehyde and an evaluation of its effects on the DNA repair process in human diploid fibroblasts. , 1986, Mutation research.

[19]  T. Skopek,et al.  Formaldehyde mutagenesis and formation of DNA-protein crosslinks in human lymphoblasts in vitro. , 1987, Mutation research.

[20]  R. Gantt.  A cell cycle-associated pathway for repair of DNA-protein crosslinks in mammalian cells. , 1987, Mutation research.

[21]  G N Cosma,et al.  The detection of DNA-protein cross-links in rat tracheal implants exposed in vivo to benzo[a]pyrene and formaldehyde. , 1988, Cancer letters.

[22]  R. Jamasbi,et al.  Growth inhibition and DNA damage induced by benzo[a]pyrene and formaldehyde in primary cultures of rat tracheal epithelial cells. , 1988, Mutation research.

[23]  T. Skopek,et al.  Molecular analysis of formaldehyde-induced mutations in human lymphoblasts and E. coli. , 1988, Environmental and molecular mutagenesis.

[24]  P. O'Connor,et al.  Isolation and characterization of proteins cross-linked to DNA by the antitumor agent methylene dimethanesulfonate and its hydrolytic product formaldehyde. , 1989, The Journal of biological chemistry.

[25]  T. Skopek,et al.  Formaldehyde-induced and spontaneous alterations in human hprt DNA sequence and mRNA expression. , 1989, Mutation research.

[26]  H. Heck,et al.  Covalent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 rats: analysis of formaldehyde and DNA by high-performance liquid chromatography and provisional pharmacokinetic interpretation. , 1989, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[27]  Kevin T. Morgan,et al.  Covalent Binding of Inhaled Formaldehyde to DNA in the Respiratory Tract of Rhesus Monkeys: Pharmacokinetics, Rat-to-Monkey Interspecies Scaling, and Extrapolation to Man , 1991 .

[28]  K T Morgan,et al.  Regional increases in rat nasal epithelial cell proliferation following acute and subchronic inhalation of formaldehyde. , 1991, Toxicology and applied pharmacology.

[29]  L. Pluta,et al.  p53 mutations in formaldehyde-induced nasal squamous cell carcinomas in rats. , 1992, Cancer research.

[30]  O R Moss,et al.  DNA-protein cross-links and cell replication at specific sites in the nose of F344 rats exposed subchronically to formaldehyde. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[31]  Joseph A. Cotruvo,et al.  Risk assessment of formaldehyde , 1994 .

[32]  R. Snapka,et al.  Aldehyde-induced protein-DNA crosslinks disrupt specific stages of SV40 DNA replication. , 1994, Carcinogenesis.

[33]  J A Swenberg,et al.  Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells. , 1996, Cancer research.

[34]  O Merk,et al.  Significance of formaldehyde‐induced DNA–protein crosslinks for mutagenesis , 1998, Environmental and molecular mutagenesis.

[35]  P. Cook.  The organization of replication and transcription. , 1999, Science.