Malarkey D E, Devereux T R, Dinse G E, Mann P C, Maronpot R R
Department of Microbiology, Pathology and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.
Carcinogenesis. 1995 Nov;16(11):2617-25. doi: 10.1093/carcin/16.11.2617.
Logistic regression analysis of age-specific prevalences for neoplastic and non-neoplastic liver lesions was used to examine treatment responses for B6C3F1 and B6D2F1 male mice continuously exposed to chlordane (55 p.p.m.) and to determine whether neoplasms were dependent on continuous exposure in the B6C3F1 mice. In order to determine if ras oncogene activation plays a role in the carcinogenicity of chlordane and whether the activation is dependent on genetic background, liver tumors from chlordane-treated B6C3F1 and B6D2F1 mice were analyzed for the presence of activating mutations in the ras oncogene. The overall liver tumor prevalence at terminal killing was nearly 100% for both strains; however, the age-specific prevalence increased more rapidly in B6C3F1 mice than in B6D2F1 mice. Tumor-bearing B6C3F1 mice had an average of two or more tumors per liver than B6D2F1 mice at their respective terminal killings (5.4 versus 3.3). When chlordane exposure was discontinued for a group of B6C3F1 mice ('stop' group) at 491 days of age, overall tumor multiplicity significantly decreased by 30% from an average of 4.4 per tumor-bearing-animal at 525 days to 3.1 at terminal killing (568 days). Over the same time period the prevalence of hepatocellular carcinomas significantly decreased from 80 to 54% and adenomas from 100 to 93% by terminal killing in B6C3F1 'stop-group' mice. Chlordane induced diffuse hepatocellular centrilobular hypertrophy, frequent multinucleate hepatocytes, toxic change and hepatoproliferative lesions composed predominantly of acidophilic hepatocytes in nearly 100% of both the B6C3F1 and B6D2F1 mice. The development of histological evidence of toxicity closely paralleled the temporal development of hepatocellular neoplasia and decreased in severity when the tumor burden was maximal. No H- or K-ras mutations were detected in the chlordane-induced hepatocellular tumors in B6C3F1 mice (15 adenomas and 15 carcinomas) or B6D2F1 mice (10 adenomas and 10 carcinomas). In conclusion, chlordane induced liver tumors in both B6C3F1 and B6D2F1 male mice by mechanisms independent of ras oncogene activation and 30% of both benign and malignant liver tumors in the B6C3F1 mice regressed after exposure was discontinued.
采用逻辑回归分析方法，对持续接触氯丹（55 ppm）的B6C3F1和B6D2F1雄性小鼠的肿瘤性和非肿瘤性肝脏病变的年龄特异性患病率进行分析，以检查其治疗反应，并确定肿瘤是否依赖于B6C3F1小鼠的持续接触。为了确定ras癌基因激活是否在氯丹的致癌作用中发挥作用，以及这种激活是否依赖于遗传背景，对氯丹处理的B6C3F1和B6D2F1小鼠的肝脏肿瘤进行分析，以检测ras癌基因中激活突变的存在情况。两种品系在终末处死时的总体肝脏肿瘤患病率均接近100%；然而，B6C3F1小鼠的年龄特异性患病率比B6D2F1小鼠增加得更快。在各自的终末处死时，携带肿瘤的B6C3F1小鼠每只肝脏的平均肿瘤数比B6D2F1小鼠多两个或更多（5.4对3.3）。当一组B6C3F1小鼠（“停止”组）在491日龄时停止接触氯丹，总体肿瘤多重性从525日龄时每只携带肿瘤动物平均4.4个显著下降30%，至终末处死（568日龄）时为3.1个。在同一时间段内，B6C3F1“停止”组小鼠中肝细胞癌的患病率从80%显著降至终末处死时的54%，腺瘤从100%降至93%。氯丹在近100%的B6C3F1和B6D2F1小鼠中诱导弥漫性肝细胞中央小叶肥大、频繁的多核肝细胞、毒性变化以及主要由嗜酸性肝细胞组成的肝增殖性病变。毒性的组织学证据的发展与肝细胞肿瘤的时间发展密切平行，并且在肿瘤负担最大时严重程度降低。在B6C3F1小鼠（15个腺瘤和15个癌）或B6D2F1小鼠（10个腺瘤和10个癌）的氯丹诱导的肝细胞肿瘤中未检测到H-或K-ras突变。总之，氯丹通过独立于ras癌基因激活的机制在B6C3F1和B6D2F1雄性小鼠中诱导肝脏肿瘤，并且在B6C3F1小鼠中，30%的良性和恶性肝脏肿瘤在停止接触后消退。
