Carcinogenicity of diethylnitrosamine in newborn, infant, and adult mice

Abstract

Modifying effects of age, sex, and mouse strain on diethylnitrosamine (DEN) carcinogenesis have been investigated in C57BL/6Jx C3HeB/FeJ F1 (B6C3F1) and C3HeB/FeJxA/J F1 (C3AF1) hybrid mice. Animals each received four IP injections of 1.5 or 3.0 micrograms DEN/g body weight. The first injections were administered on days 1, 15, or 42 of life. Subsequent treatments were delivered at 3-, 6-, and 6-day intervals, respectively. Mice were kept under observation for the remaining life-span. DEN treatment induced tumors in liver, lungs, and forestomach in descending order of frequency. The majority of the induced liver tumors were hepatocellular carcinomas. Animals treated as newborns and infants developed significantly more liver tumors than animals that were treated as young adults. Newborn and infant females developed liver tumors at a later age (B6C3F1) and with a lower incidence (C3AF1) than similarly treated males. The B6C3F1 mice developed more hepatocellular carcinomas and a higher rate of pulmonary metastases than the C3AF1 mice. In contrast, C3AF1 mice developed lung tumors with a higher incidence and multiplicity than B6C3F1 hybrids. Forestomach tumors were observed also with a slightly but significantly higher incidence in C3AF1 mice.

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

“…DEN generates ROS and causes DNA damage, which contributes to the development of HCC. 9,24 As Casp2 −/− mice are more susceptible to oxidative stress-induced damage to lipids, DNA and protein, 24,25 these parameters were measured in liver (Figures 2a, b and d). While no difference in lipid peroxidation (MDA) was observed between WT and Casp2 −/− DEN-injected mice (Figure 2a Liver damage and inflammation is often accompanied by increases in hepatic cell death and proliferation.…”

“…Hepatocarcinogenesis is a multistep process that can be caused by a number of agents that ultimately lead to malignant transformation of hepatocytes. [7][8][9][10]29 HCC induction by DEN is a commonly utilised mouse model. 9,10 DEN is an alkylating agent that induces DNA damage by reacting with nucleophiles such as DNA bases.…”

“…Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression.…”

“…9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. [7][8][9][10] It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC.…”

“…9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. [7][8][9][10] It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. [11][12][13] While loss of apoptosis would indirectly favour proliferation, this is not universally true, for example loss of PUMA, or hepatocyte-specific deletion of Bid, impedes HCC by preventing compensatory proliferation.…”