Eldridge S R, Goldsworthy S M
Pathology Associates International, Durham, North Carolina 27713, USA.
Fundam Appl Toxicol. 1996 Aug;32(2):159-67. doi: 10.1006/faat.1996.0119.
Increasing emphasis is being placed on mode of action for chemical carcinogens as an important consideration for risk assessment. Many rodent carcinogens appear to act through nongenotoxic mechanisms, such as induced cell proliferation. Information on cell proliferation rates based on species, age, gender, tissue, and choice of marker will provide a foundation for incorporating such measurements into rodent toxicity studies. Cell proliferation was evaluated in liver, kidney, skin, and forestomach of control male and female B6C3F1 mice and F344 rats at 7, 10, 13, and 20 weeks of age. Proliferating cell nuclear antigen (PCNA), an endogenous cell proliferation marker, and bromodeoxyuridine (BrdU) administered by ip injection 2 hr before euthanization were compared as markers of cell proliferation. Only in liver were BrdU and PCNA labeling indices (LIs; S phase only) statistically similar. As expected, the PCNA proliferating index (PI; G1 + S + G2 + M phases) was consistently greater than the S phase LI in all tissues examined. Age-related differences in LI were evident in liver and kidney, whereas LIs in the forestomach and skin were not age- dependent. In all tissues examined, gender- and species-related differences in cell proliferation were detected. Although BrdU and PCNA LIs were often statistically different, they both provided a useful indication of cell proliferation rates in the tissues examined. These results provide potentially useful information for designing rodent toxicity studies and biological models of carcinogenesis.
化学致癌物的作用模式作为风险评估的一个重要考虑因素，正受到越来越多的重视。许多啮齿动物致癌物似乎通过非遗传毒性机制起作用，例如诱导细胞增殖。基于物种、年龄、性别、组织和标记物选择的细胞增殖率信息，将为把此类测量纳入啮齿动物毒性研究提供基础。在7、10、13和20周龄的对照雄性和雌性B6C3F1小鼠以及F344大鼠的肝脏、肾脏、皮肤和前胃中评估细胞增殖情况。比较了增殖细胞核抗原（PCNA），一种内源性细胞增殖标记物，以及在安乐死2小时前腹腔注射的溴脱氧尿苷（BrdU）作为细胞增殖的标记物。仅在肝脏中，BrdU和PCNA标记指数（LI；仅S期）在统计学上相似。正如预期的那样，在所有检查的组织中，PCNA增殖指数（PI；G1 + S + G2 + M期）始终大于S期LI。肝脏和肾脏中LI的年龄相关差异明显，而前胃和皮肤中的LI与年龄无关。在所有检查的组织中，检测到了细胞增殖的性别和物种相关差异。尽管BrdU和PCNA LI通常在统计学上不同，但它们都为所检查组织中的细胞增殖率提供了有用的指示。这些结果为设计啮齿动物毒性研究和致癌生物学模型提供了潜在有用的信息。
