DNA-PROTEIN CROSS-LINKS AND CELL REPLICATION AT SPECIFIC SITES IN THE NOSE OF F344 RATS EXPOSED SUBCHRONICALLY TO FORMALDEHYDE
DNA-PROTEIN CROSS-LINKS AND CELL REPLICATION AT SPECIFIC SITES IN THE NOSE OF F344 RATS EXPOSED SUBCHRONICALLY TO FORMALDEHYDE
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DOI：
10.1006/faat.1994.1137
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发表时间：
1994-11-01
期刊：
影响因子：
--
通讯作者：
HECK, HD
中科院分区：
文献类型：
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作者：
CASANOVA, M;MORGAN, KT;HECK, HD
长期暴露于高浓度（大于或等于 6 ppm）甲醛 (HCHO) 会诱导 F344 大鼠细胞增殖、鳞状上皮化生和鳞状细胞癌。为了评估与 HCHO 暴露相关的癌症风险，在首次暴露（之前未暴露）的大鼠和猴子中形成的 DNA-蛋白质交联 (DPX) 已被用作内部剂量的替代。由于亚长期暴露的动物中 DPX 的量可能有所不同，因此确定了预暴露于 HCHO 对急性 DPX 产量（单次暴露后的 DPX 浓度）和累积 DPX 产量（重复暴露后的 DPX 浓度）的影响。雄性 F344 大鼠预先暴露 (PE) 于 0.7、2、6 或 15 ppm 的 HCHO（6 小时/天，5 天/周，11 周 + 4 天）。幼稚（N）大鼠暴露于室内空气。在第 12 周的第 5 天，将 PE 和 N 大鼠同时暴露于 (HCHO)-C-14（3 小时），其浓度与预暴露的浓度相同。在鼻侧鼻道 (LM)（HCHO 生物测定中的高肿瘤位点）和内侧和后鼻道 (M:PM)（生物测定中的低肿瘤位点）的粘膜内层中测定急性 DPX 产量和细胞复制（C-14 掺入 DNA）。 LM 中的 DPX 产量大约是 M:PM 的六倍。在 0.7 和 2 ppm 浓度下，PE 和 N 大鼠的任一组织均未检测到差异。在 6 和 15 ppm 时，PE 大鼠 LM 中的急性 DPX 产量约为 N 大鼠的一半，但在 M:PM 中未检测到差异。在 6 ppm（仅 LM）尤其是 15 ppm（LM 和 M:PM）下，PE 大鼠中的细胞增殖被诱导。通过测定蛋白质中 DNA 提取率的降低来间接测量累积 DPX 产量。 PE 大鼠如上所述预先暴露于 6 或 10 ppm，而 N 大鼠则暴露于室内空气。然后将两组（PE 和 N）暴露于相同浓度的未标记 HCHO（3 小时）。两组中 DPX 产量均呈浓度依赖性增加，但 PE 大鼠中的产量小于 N 组大鼠，表明 PE 大鼠中未发生 DPX 积累。结果表明，在浓度小于或等于 2 ppm 时，N 和 PE 大鼠在 DPX 的形成方面是相当的。当浓度大于或等于 6 ppm 时，N 和 PE 大鼠并不相同，但这种高剂量效应对线性多阶段模型得出的低剂量癌症风险估计的影响很小。 (C) 1994 年毒理学会。
Chronic exposures to high concentrations (greater than or equal to 6 ppm) of formaldehyde (HCHO) induce cell proliferation, squamous metaplasia, and squamous cell carcinomas in F344 rats. To assess the cancer risk associated with HCHO exposure, DNA-protein cross-links (DPX) formed in a single exposure of naive (previously unexposed) rats and monkeys have been used as a surrogate for the internal dose. Since the quantity of DPX may differ in subchronically exposed animals, the effects of preexposure to HCHO on the acute DPX yield (concentration of DPX following a single exposure) and the cumulative DPX yield (concentration of DPX following repeated exposures) were determined. Male F344 rats were preexposed (PE) to 0.7, 2, 6, or 15 ppm of HCHO (6 hr/day, 5 days/week, 11 weeks + 4 days). Naive (N) rats were exposed to room air. On the 5th day of the 12th week, PE and N rats were simultaneously exposed (3 hr) to (HCHO)-C-14 at the same concentrations used for preexposure. Acute DPX yields and cell replication (incorporation of C-14 into DNA) were determined in the mucosal lining of the nasal lateral meatus (LM) (high tumor site in HCHO bioassay) and the medial and posterior meatuses (M:PM) (low tumor site in bioassay). DPX yields in the LM were approximately sixfold higher than in the M:PM. At 0.7 and 2 ppm, no differences between PE and N rats were detected in either tissue. At 6 and 15 ppm, acute DPX yields in the LM of PE rats were approximately half those of N rats, but no differences were detected in the M:PM. Cell proliferation was induced in PE rats at 6 ppm (LM only) and especially at 15 ppm (LM and M:PM). Cumulative DPX yields were measured indirectly by determining the decrease in extractability of DNA from proteins. PE rats were preexposed to 6 or 10 ppm as above, while N rats were exposed to room air. Both groups (PE and N) were then exposed (3 hr) to the same concentration of unlabeled HCHO. DPX yields increased in a concentration-dependent manner in both groups, but the yields were smaller in PE than N rats, suggesting that no accumulation of DPX occurred in PE rats. The results demonstrate that at concentrations less than or equal to 2 ppm, N and PE rats are equivalent with respect to the formation of DPX. At concentrations greater than or equal to 6 ppm, N and PE rats are not equivalent, but the impact of this high-dose effect on low-dose cancer risk estimates derived with the linearized multistage model is small. (C) 1994 Society of Toxicology.