Transgenerational carcinogenesis: induction and transmission of genetic alterations and mechanisms of carcinogenesis

Abstract

Parental exposure, i.e. germ cell exposure to radiation and chemicals, increased the incidence of tumors and malformations in the offspring, and the germ-line alterations that cause cancer are transmissible to further generations. However, tumor incidences were 100-fold higher than those of ordinary mouse mutations and there were apparent strain differences in the types of induced tumors. In human, higher risk of leukemia is reported in the children of fathers who had been exposed to radionuclides at the nuclear reprocessing plants or to diagnostic doses of radiation. However, these findings in mice and men have not been confirmed in the children of atomic bomb survivors in Hiroshima and Nagasaki. Another important finding was that germ-line exposure was very weakly tumorigenic by itself. However, the transmissible alterations caused persistent hypersensitivity to tumor induction in the offspring, e.g. enhanced by postnatal treatment with tumor promoting/carcinogenic agents. The above results suggest that transmissible alterations might be imprinted in germ cells for the future development of cancer by the postnatal environment. Many gene loci concerning immunological, biochemical and physiological function might be involved, and the cumulative changes in such genes may slightly elevate or enhance tumor incidences, although mutations of tumor suppressor genes such as p53 were also detected in some offspring and genomic instability may modify tumor occurrence in transgenerational manner. In fact, Gene Chip analysis showed suppression and/or over-expression of many functional genes rather than cancer-related genes in the preconceptionally irradiated cancer prone progeny.

Introduction

Radiation and chemicals are known to produce visible and lethal mutations in germ cells of higher plants and animals. In mice, parental exposure to radiation and chemicals also induced tumors and congenital malformations [1], [2], [3], [4], [5]. The increase in the incidence of malformations has been confirmed by Kirk and Lyon [6] with radiation, and risk of the offspring from father’s exposure to toxic agents is suggested [7], [8]. Preconceptional exposure of females also induces such defects in the offspring [1], [2], [3], [9]. The first and large scale mouse experiments on tumor induction in the offspring after parental exposure to radiation were carried out by Nomura [2], [3]. Dose dependent increases of tumors were observed in the F₁ offspring of male and female ICR mice exposed to acute doses of X-rays (0.36–5.04 Gy). Postmeiotic stages of germ cells were twice as sensitive to tumor induction as the spermatogonial stage. Oocytes were resistant to low doses (∼1 Gy) of X-rays but very sensitive to higher doses. Protracted parental irradiation (0.36 Gy at 2 h intervals) at the spermatogonia and mature oocyte stages significantly reduced the tumorigenic effects of radiation in the offspring, compared to single irradiation with the same total doses (2.16, 3.6 and 5.04 Gy) [2], [3]. However, such reduction was not observed, when postmeiotic stages were irradiated. The pattern of the radiation sensitivity of germ cell stages for tumor induction was similar to that for ordinary mouse mutations [10], [11], [12], [13], [14]. Furthermore, significantly high incidences of tumors were observed in the F₂ generation only when F₁ progeny had tumors, suggesting that germ-line alterations causing tumors transmitted to the next generation [2], [3]. However, both induced and spontaneous incidences of tumors are 100-fold higher than those of ordinary mouse mutations [3], [10], [11], [12], [13], [14]. Doubling dose of tumor-causing alteration in spermatogonia was about 1.5 Gy for adult type tumors in the lung and ovary [5]. Postnatal treatment of irradiated offspring with tumor promoting agents, urethane, etc. enhanced tumor incidences [4], [15]. Some of the original findings by Nomura were confirmed with different strains of mice N5, LT, etc. with radiation and chemicals [1], [2], [3], [5], [16]. However, the above studies have not been supported by a large epidemiological survey in the children of atomic bomb survivors in Hiroshima and Nagasaki until now.

In this review, evidences for the induction and transmission of genetic alterations and a possible mechanism for the induction of transgenerational carcinogenesis are presented.