The effects of X-irradiation, N-ethyl-N-nitrosourea or combined treatment on O⁶-alkylguanine-DNA alkyltransferase activity in fetal rat brain and liver and the induction of CNS tumours

Abstract

Wistar rats were treated in utero on day 16 of gestation either by X-irradiation (1 and 2 Gy), N-ethyl-N-nitrosourea (ENU, 50 mg/kg), or both in combination. The O6-alkylguanine-DNA alkyltransferase (AT) activity of the fetal brain and liver was analyzed and long-term observations were made to reveal any relationship between the O6-ethylguanine repair capability and tumour incidence in the organs of the offspring. The AT activity in the brain was affected to the same extent in the fetuses as in the dams. There was a 60.9% decrease in AT activity in fetuses 24 h after ENU treatment. This correlates with a significant increase in the incidence of brain tumours in the treated offspring (44.1%) compared to control animals. The inductive effect of X-irradiation on AT activity (131.3% for 1 Gy and 201.6% for 2 Gy) corresponded in turn with a reduction of the incidence of tumours after the combined treatment (26.8% and 8.3% tumour incidence, 103.1% and 157.8% AT activity). In the liver of the rat fetuses, there was generally no effect of treatment on AT activity in contrast to the results obtained for the dams, where an increased AT activity (127.70% and 157.4% after X-irradiation, 149.0% and 156.1% after combined treatment) was observed. There were no tumours of the liver observed in the offspring after either treatment alone or after combined treatment. Comparing biochemical and morphological results, it is suggested that X-irradiation of rat fetuses--with relatively low doses--and subsequent treatment with the ethylating carcinogen ENU, could significantly reduce the incidence of brain tumours in adult life. This is possibly a result of the corresponding induction of AT.

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma

“…The present risk assessment of combined exposure is consistent with a simple additive effect of the two carcinogens, but previously reported animal experiments showed that combined exposure could have either synergistic or antagonistic effects on cancer development [3,10,11,[17][18][19]. In our current study, we found both dose-dependent synergistic and antagonistic effects of X-ray/ENU exposure, suggesting the importance of the ENU and radiation doses for risk assessment.…”

“…For example, a synergistic effect of these agents was reported in mouse T-cell lymphomas [10,11], mouse liver and ovary tumors [12], rat hepatocyte foci [13], and rat intestinal tumors [14]; while an antagonistic effect, also known as an adaptive response or a hormetic effect [15,16], was found for rat central nervous system [17,18] and brain tumors [19]. Thus, the nature of interaction between combined treatments varies between experiments.…”

Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation

“…Clearly this effect requires substantiation with a large number of patients receiving only TBI. It is interesting to note that in rodents, ATase activity in a number of tissues was increased by a single dose of ionising radiation (Margison et al, 1985;Stammberger et al, 1990). Changes in the specific activity of peripheral lymphocyte…”

Combined Effect of Ionizing Radiation and Alkylating Agents on Cancer Induction

“…Similarly, incidence of brain tumors, which were induced by ENU treated in utero, decreased after combined treatment with pre-exposed X-rays (1 and 2 Gy), showing antagonistic eŠect. The reduction of tumor incidence corresponded with the inductive eŠect of X-irradiation on O 6 -alkylguanine-DNA alkyltransferase (ATase), suggesting a protective role of IR by inducing ATase for subsequent ENU treatment (20). Induction of ATase by IR has been frequently observed in several tissues in vivo.…”

“…Non-genotoxic chemicals may aŠect cell proliferation, diŠerentiation and senescence. The experimental data on combined exposures are mostly accumulated for alkylating agents such as N-methyl-N-nitrosourea (MNU), N-ethyl-N-nitrosourea (ENU), 1,2-dimethylhidrazine (DMH), diethylnitrosamine (DEN) etc (15)(16)(17)(18)(19)(20)(21)(22).…”