Possible role of genetic predisposition in multigeneration carcinogenesis

A peculiar phenomenon in experimental transplacental carcinogenesis is that in certain animal species or strains, and with certain types of carcinogens, a tumorigenic risk is observed not only in the F1 generation but also in subsequent F2 and even F3 generations when only the P generation has been exposed to a carcinogen. Additionally, in many cases, specific types of organs tend to be involved. For example, lung tumours are most common in P, F1 and F2 generations of Swiss, ICR, MA and CD-1 mice after exposure of the pregnant P generation to 7,12-dimethylbenz[a]anthracene (DMBA), urethane, DMBA and diethylstilboestrol, respectively. In such mice, the mammary glands, lymphatic tissues and ovaries are also frequently involved. Recently, two-stage tumorigenesis in skin with a phorbol acetate as promoter was transmitted to F2 descendants born of F1 SHR mice exposed transplacentally to DMBA. In WKA, BD IV and BD VI rats, nervous tissues seem to be prone to tumour development in F2 and/or F3 descendants born of F1 exposed transplacentally to N-methyl-N-nitrosourethane, N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea (ENU), respectively. In F344 strain rats, however, two-stage genesis of preneoplastic foci in the liver with 2-acetylaminofluorene (2-AAF) as the promoter failed to be transmitted to F2 and F3 generations from the F1 generation, which developed the preneoplastic hepatocellular foci after prenatal exposure to ENU followed by postnatal promotion by 2-AAF. Our own recent experiments with Syrian hamsters, in which multigeneration transmission of organ-specific (tracheal epithelium) tumorigenicity of N-nitrosodiethylamine was investigated, have also failed to show this phenomenon in F2 and F3 descendants. However, various field studies on pedigrees with frequently affected siblings indicate the existence of a heritable predisposition to tumour development over more than two generations. The organs involved include ovaries, mammary glands, stomach, lympho- and myelogenic systems, skin and nervous system. Interestingly, little or no such evidence has been found in the liver, respiratory tract (except for the nasopharyngeal region) or urinary tract. In the light of these experimental and human observations, the authors are currently inclined to hypothesize a heritable predisposition to tumour development in organs specific to animal species and strains, or certain families in human cases, for explaining the mechanisms underlying multigeneration transmission of chemical carcinogenicity.