Possible carcinogenic effects of X-rays in a transgenerational study with CBA mice

Abstract

A lifetime experiment using 4279 CBA/J mice was carried out to investigate whether the pre-conceptual exposure of sperm cells to X-ray radiation or urethane would result in an increased cancer risk in the untreated progeny, and/or increased susceptibility to cancer following exposure to a promoting agent. The study consisted of four main groups, namely a control group (saline), a urethane group (1 mg/g body wt) and two X-ray radiation groups (1 Gy, 2 Gy). At 1, 3 and 9 weeks after treatment, the males of these four parental groups were mated with untreated virgin females. The offspring of each parental group was divided into two subgroups: one received s.c. urethane (0.1 mg/g body wt once) as a promoter, the other saline, at the age of 6 weeks. All animals were evaluated for the occurrence of tumours. K-ras oncogene and p53 tumour suppressor gene mutations were investigated in frozen lung tumour samples. The female offspring of male parents exposed to X-rays 1 week before their mating showed a trend towards a higher tumour incidence of the haematopoietic system than the F1 controls. In addition, a higher percentage of bronchioloalveolar adenocarcinomas in male offspring born to irradiated paternals mated 1 week after X-ray treatment points to a plausible increased sensitivity of post-meiotic germ cell stages towards transgenerational carcinogenic effects. On the other hand, no increased tumour incidence and malignancy were observed in the offspring born to irradiated paternals mated 3 and 9 weeks after X-ray treatment. Paternal urethane treatment 1, 3 and 9 weeks prior to conception did not result in significantly altered incidence or malignancy of tumours of the lung, liver and haematopoietic tissue in the offspring. K-ras mutations increased during tumour progression from bronchioloalveolar hyperplasia to adenoma. Codon 61 K-ras mutations were more frequent in lung tumours of urethane-promoted progeny from irradiated parents than from control parents. P53 mutations were absent from these lung alterations.

Paternal transmission of genetic damage: findings in animals and humans

“…In the first of these, no X‐ray treatment‐related increase in lung tumours among the progeny of C3/HeH mice was detected (see above) and no effect was found on susceptibility to urethane‐induced tumours (Cattanach et al ., 1998). The second, also described above, likewise failed to show an enhancing effect of urethane treatment of the offspring on tumour rates among the progeny of X‐ray‐treated male CBA/J mice (Mohr et al ., 1999).…”

“…Similar, significant (though less marked effects) were found after exposure to only 12.5 cGy 252 Cf fission neutrons (Shoji et al ., 1998). Most recently, a study of 1 Gy or 2 Gy X‐rays claimed possible weak effects on tumours of the haemopoietic system (in females) and bronchioalveolar tumours (in males) among the offspring (Mohr et al ., 1999).…”

Sperm epigenetic profile and risk of cancer

“…Radiation induces phenotypic and genotypic alterations in the progeny of treated males. Such genotypic alterations may predispose the progeny of irradiated parents to an increased risk of genetic diseases, infertility, or cancer [21,29,30]. Moreover, the consequences of sperm chromatin damage are not limited to the progeny of males exposed to the toxic agent, and several future generations can be affected.…”

Critical Windows of Exposure for Children's Health: Cancer in Human Epidemiological Studies and Neoplasms in Experimental Animal Models

“…Thus, preconceptional carcinogenesis for the nervous system in rats by ethylnitrosourea (ENU) (129) could not be demonstrated with statistical significance in a later study (130). Preconceptional exposure to X rays of ICR or SHR (Swiss) mice led to increased lung tumors or increased susceptibility to postnatal induction of these tumors in offspring (131)(132)(133), but this effect could not be reproduced in BALB/c (134) or C3H (135) mice and only minimal effects were seen in CBA mice (136). X-irradiation of the spermatogonia of N5 mice resulted in increased incidence of leukemia in offspring (137); mice of this same strain were treated with X rays or tritium at the postmeiotic stage several decades later in another laboratory, and the treatment had a borderline effect on leukemia incidence (138).…”