Shigano Miyuki, Takashima Rie, Satomoto Kensuke, Sales Henri, Harada Ryoko, Hamada Shuichi
Safety Assessment Department, Kashima Laboratories, Mediford Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki, 314-0255, Japan.
Nippon Kayaku Co., Ltd., 2-1-1 Marunouchi, Chiyoda-Ku, Tokyo, 100-0005, Japan.
Genes Environ. 2024 Aug 23;46(1):17. doi: 10.1186/s41021-024-00311-x.
Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer commonly used in a wide variety of products, including medical devices. It is rapidly metabolized in the liver into various metabolites upon absorption through oral ingestion, dermal absorption, and inhalation. DEHP is classified as a non-genotoxic hepatocarcinogen in rodents, as its chronic exposure has been associated with the development of liver cancer in these animals, but most genotoxicity studies have been negative. Epidemiologic studies in humans suggest that long-term high intakes of DEHP may be a risk factor for liver dysfunction. The repeated-dose liver micronucleus (RDLMN) assay is a well-established method for assessing chromosomal changes caused by hepatic genotoxins and/or carcinogens. It is particularly valuable for detecting substances that undergo metabolic activation, especially when the metabolite has a short half-life or does not reach the bone marrow effectively. Therefore, we investigated whether the RDLMN assay could detect DEHP-induced micronucleus formation in the liver following a 14 or 28-day treatment.
We report that the RDLMN assay demonstrated an increased frequency of hepatic micronuclei in rats exposed to DEHP for 14 or 28 days. The increases in micronuclei correlated with hepatomegaly, an established response to phthalates in the liver. Conversely, no such increases were observed in the micronucleus assay using bone marrow from these rats.
The detection of DEHP-induced micronuclei by the RDLMN assay suggests that this assay could detect the potential genotoxicity and hepatocarcinogenicity of DEHP. It also demonstrated the utility of the RDLMN assay in identifying metabolically activated hepatic carcinogens.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种常用于各种产品（包括医疗设备）的增塑剂。通过口服摄入、皮肤吸收和吸入吸收后，它在肝脏中迅速代谢为各种代谢物。DEHP在啮齿动物中被归类为非基因毒性肝癌致癌物，因为其长期暴露与这些动物的肝癌发生有关，但大多数基因毒性研究结果为阴性。对人类的流行病学研究表明，长期高剂量摄入DEHP可能是肝功能障碍的一个风险因素。重复剂量肝脏微核（RDLMN）试验是一种成熟的评估肝脏基因毒素和/或致癌物引起的染色体变化的方法。它对于检测经历代谢活化的物质特别有价值，尤其是当代谢物半衰期短或不能有效到达骨髓时。因此，我们研究了RDLMN试验能否检测14天或28天治疗后DEHP诱导的肝脏微核形成。
我们报告，RDLMN试验显示暴露于DEHP 14天或28天的大鼠肝脏微核频率增加。微核增加与肝肿大相关，肝肿大是肝脏对邻苯二甲酸盐的一种既定反应。相反，在使用这些大鼠骨髓的微核试验中未观察到这种增加。
RDLMN试验检测到DEHP诱导的微核表明该试验可以检测DEHP的潜在基因毒性和致癌性。它还证明了RDLMN试验在识别代谢活化的肝脏致癌物方面的实用性。
