DNA Methylation, Cell Proliferation, and Histopathology in Rats Following Repeated Inhalation Exposure to Dimethyl Sulfate

Abstract

Dimethyl sulfate (DMS) is an alkylating agent that is carcinogenic to the respiratory tract of rodents. DNA adducts, cell proliferation, and histopathology were assessed in rats to better understand the molecular dosimetry and tissue dynamics associated with repeated inhalation exposure to DMS. For DNA methylation, rats were exposed to DMS vapor 6 h/day for up to 10 days to 0.0, 0.1, 0.7 and 1.5 ppm. N7-Methylguanine and N3-methyladenine were detected in neutral thermal hydrolysates of DNA isolated from respiratory tract tissues by high-performance liquid chromatography (HPLC) using fluorescence and ultraviolet (UV) detection. DNA methylation was greatest in DNA isolated from nasal respiratory mucosa, less in olfactory, and little was found in lung. N7-Methylguanine levels in respiratory mucosa approached steady-state levels by day 5, and N7-methylguanine persistence following exposure for 5 consecutive days was also determined. Loss of N7-methylguanine from respiratory and olfactory mucosa appeared to follow first-order kinetics. N3-Methyladenine levels were at or below detection limits in all samples. The effect of DMS on histopathology and cell proliferation in the nasal epithelium was also investigated. Rats were exposed nose-only for 2 wk to DMS vapor at concentrations of 0, 0.1, 0.7, or 1.5 ppm. Inhalation exposure to DMS induced degenerative and inflammatory changes in nasal epithelium at >or=0.7 ppm. Cell proliferation evaluations showed a trend towards an increased response at 1.5 ppm. These experiments demonstrate that DMS can induce cytotoxic and proliferative effects and is a potent methylating agent of the nasal mucosa in vivo. These experiments will provide data for the development of dosimetry models useful for risk extrapolation.

Interspecies Dose Extrapolation for Inhaled Dimethyl Sulfate: A PBPK Model-Based Analysis using Nasal Cavity N7-Methylguanine Adducts

“…The hypothesized mode of action for DMS-induced respiratorytract tumors in rats is that the formation of N 7 -methylaguanine adducts leads to base substitutions and mutations through an apurinic site intermediate. Our companion article (Mathison et al, 2004) further shows that DMS exposure can cause cytotoxicity and proliferative lesions of the nasal epithelium. Cytotoxicity-induced cell division potentiates the carcinogenic process by increasing the fixation of mutations and the expansion of altered cells.…”

“…In the case of DMS, the selection of a dose metric is restricted by the absence of data describing the relationship between the carcinogenicity and mutagenicity of DMS and its adduct profile. The most promutagenic adduct, O 6 mG, was present below detection levels in the study that provides the characterization of adduct levels (Mathison et al, 2004) and cannot be used as a tissue dose metric, although it may contribute to the mutagenicity of DMS. Of the remaining adducts, the N 7 mG adduct has an established mutagenic potential and the levels following exposure to DMS has been characterized to the greatest extent.…”

“…Indeed, we have observed such a gradient with respect to cytotoxic lesions and DNA adduct dosimetry in the nasal cavity (Mathison et al, 2004).…”

“…The rate of hydrolysis of DMS was estimated from the literature (Robertson & Sugamori, 1996). Mathison and coworkers have characterized N 7 mG adduct accumulation and removal in rat respiratory and olfactory mucosa after inhalation exposure to 0.1-1.5 ppm DMS (Mathison et al, 2004). The first-order rate constant for adduct loss in the respiratory and olfactory tissue was estimated by fitting the model-derived adduct levels to a subset of these experimentally measured DNA adduct levels.…”

Chronic diseases and early exposure to airborne mixtures: Part III. Potential origin of pre-menopausal breast cancers

“…The alkylating action of DMS and its carcinogenicity have been described (van Duuren et al, 1974;Hoffman, 1980;Mathison et al, 2004). The potential toxic pathways of DMS in an occupational setting are inhalation, dermal and gastrointestinal (Rippey and Stallwood, 2005).…”