DNA-Protein Cross-links and Cell Replication at Specific Sites in the Nose of F344 Rats Exposed Subchronically to Formaldehyde

Casanova, Mercedes; Morgan, Kevin T.; Gross, Elizabeth A.; Moss, Owen R.; Heck, Henry d’A.

doi:10.1006/faat.1994.1137

Cited by 132 publications

(80 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, they cannot differentiate between exogenous and endogenous formaldehyde-induced DPCs. Other studies have shown a rapid decline of the formaldehyde-induced DPCs in cell cultures, and no accumulation of DPCs was observed in rats after repeated exposure (Casanova et al, 1994;Grafstrom et al, 1984;Shoulkamy et al, 2012). Further evidence indicates that the major portions of formaldehyde-induced DPCs are lost from lymphocytes through spontaneous (Dunnett, 1964).…”

Section: Discussionmentioning

confidence: 92%

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

View full text Add to dashboard Cite

Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N 2-hydroxymethyl-dG (N 2 -HOMedG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicityinduced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N 2 -HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [ 13 CD 2 ]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t 1/2 ) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N 2 -HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency's Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair.

show abstract

Section: Discussionmentioning

confidence: 92%

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

View full text Add to dashboard Cite

show abstract

“…A number of animal and human studies have shown a link between exposure to FA and DPC (Casanova et al, 1994(Casanova et al, , 1996Shaham et al, 2003). Casanova et al (1994) conducted experiments with rats and monkeys and found that rate of DPC formation was proportional to the tissue concentration of FA.…”

Section: Discussionmentioning

confidence: 98%

“…Casanova et al (1994) conducted experiments with rats and monkeys and found that rate of DPC formation was proportional to the tissue concentration of FA. DPC in peripheral blood lymphocytes of workers exposed to high FA as biomarkers has also been advocated by Shaham et al (2003).…”

Section: Discussionmentioning

confidence: 98%

Quantitation of normal and formaldehyde‐modiﬁed deoxynucleosides by high‐performance liquid chromatography/UV detection

Zhong

Hee

2004

Biomedical Chromatography

View full text Add to dashboard Cite

A sensitive and selective method was developed for the first time to quantify simultaneously the normal and formaldehyde (FA)-modified bases in human placental DNA treated with 100 ppm FA for 20 h at 37 degrees Celsius. Digestion of DNA to deoxynucleosides with DNase I, phosphodiesterase and alkaline phosphatase occurred in that order with centrifugation steps. The normal and FA-modified deoxynucleosides were then resolved from one another and reagent blank interferences to produce selective separation through high performance liquid chromatography-ultraviolet detection at 254 nm. A C(18) reversed-phase column facilitated the resolution using 5 mm ammonium acetate and a gradient of 0-6% methanol at fl ow rates of 0.3-1.4 mL/min before column cleaning. The lower quantifiable limits for deoxyadenosine, deoxyguanosine, deoxycytidine, thymidine, N(6)-hydroxymethyldeoxyadenosine (N(6)-dA), N(2)-hydroxymethyldeoxyguanosine (N(2)-dG) and N(4)-hydroxymethyldeoxycytidine (N(4)-dC) were 11, 7.6, 12, 15, 10, 10 and 22 pmol, respectively. The abundance order of the modified deoxynucleosides was N(6)-dA > N(2)-dG > N(4)-dC. dT did not form hydroxymethyl derivatives. The respective concentrations were about 6.0, 10.0 and 23 pmol of modified deoxynucleosides in 80 micro g of human placental DNA after treatment with 100 micro g/mL of formalin for 20 h at 37 degrees Celsius. The stabilities of N(6)-dA and N(2)-dG were much better at -20 degrees Celsius than at 25 degrees Celsius, where the respective halftimes were about 50.1 and 21.0 h.

show abstract

“…To date, the application of DPX to human risk assessment has used these cross-links solely as a molecular dosimeter (55). It has recently been shown, however, that DPX yields are approximately 6 times higher in the lateral meatus (site of highest SCC frequency) compared to regions with a low SCC yield (17). This research, which provides further support for a mechanistic relationship between formaldehyde-induced DPX and cancer, was a direct consequence of tumor mapping studies (97).…”

Section: Introductionmentioning

confidence: 99%

Review Article: A Brief Review of Formaldehyde Carcinogenesis in Relation to Rat Nasal Pathology and Human Health Risk Assessment

Morgan

1997

Toxicol Pathol

View full text Add to dashboard Cite

The 1980 report that inhaled formaldehyde induced nasal squamous cell carcinomas in rats had a significant societal impact and resulted in extensive research in the fields of rodent nasal pathology and human cancer risk assessment. This article presents an overview of the evolution of these events. It is concluded that the nasal passages of humans and rats are fundamentally identical biological target organs. Nevertheless, in the case of human health risk assessment, minor differences between these species may be critically important. Special attention should be paid to interspecies differences in nasal dosimetry and local metabolism; thus, chemical toxicity data derived from rats require careful interpretation when used for human risk assessments. In the case of formaldehyde, it is recommended that lowconcentration (≤2 ppm airborne exposure) extrapolation, where no tissue damage is observed, be uncoupled from the responses at high concentrations (≥6 ppm), where epithelial degeneration, regenerative cell replication, and inflammation appear to be essential driving forces in formaldehyde carcinogenesis. The presence of treatment-related nasal lesions in rats following exposure to chemicals should always be treated as an indication of a potential human health risk, whether exposure is by the inhalation, oral, or dermal route.

show abstract

DNA-Protein Cross-links and Cell Replication at Specific Sites in the Nose of F344 Rats Exposed Subchronically to Formaldehyde

Cited by 132 publications

References 0 publications

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Quantitation of normal and formaldehyde‐modiﬁed deoxynucleosides by high‐performance liquid chromatography/UV detection

Review Article: A Brief Review of Formaldehyde Carcinogenesis in Relation to Rat Nasal Pathology and Human Health Risk Assessment

Contact Info

Product

Resources

About