Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes

Abstract

This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and on-going) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.

Epigenetic changes and nontargeted radiation effects—Is there a link?

“…Early studies of these transgeneration effects used various tests such as the specific locus, dominant lethal, and heritable translocation assays [Generoso et al, 1980;Russell and Kelly, 1982;Green et al, 1987;Russell et al, 1998]. Other studies focused on heritable alterations in cancer incidence and teratogenesis following the parental preconception irradiation [Mohr et al, 1999;Pils et al, 1999;Nomura, 2003;Nomura et al, 2004;Dasenbrock et al, 2005]. In addition to this classic evidence for transmitted effects, it is now apparent that risks to the progeny of irradiated parents also include transgeneration genomic instability [Carls and Schiestl, 1999;Mohr et al, 1999;Barber et al, 2002Shiraishi et al, 2002;Dubrova, 2003a,b;Morgan, 2003b;Niwa, 2003;Nomura, 2003;Nomura et al, 2004;Slovinska et al, 2004;Dasenbrock et al, 2005;Tawn, 2005;Singer et al, 2006].…”

Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer

“…If therapy-induced DNA damage is misrepaired, this can initiate second tumor development. Genetic predisposition may lead to increased chromosomal instability after radiation or chemotherapy [5], [11], [12]. Only in very rare cases of second childhood malignancy a genetic instability syndrome such as Fanconi anaemia, ataxia teleangiectasia or xeroderma pigmentosum has been diagnosed [10].…”

Dioxin induction of transgenerational inheritance of disease in zebrafish

“…Adverse effects have included increased congenital abnormalities, decreased survival, differences in sex ratios of offspring, and decreased reproductive function and fertility in both males and females (Wolf et al , 1999; Nomura et al , 2004; Ikeda et al , 2005a and b; King-Heiden et al , 2009; Ding et al , 2011). Transgenerational effects of TCDD exposure have now been observed in mice, rats and zebrafish (Bruner-Tran and Osteen, 2011; Manikkam et al , 2012a and b; Nilsson et al , 2012; Baker et al , 2014).…”