one considers the fact that the primary reasons for considering naturally occurring developmental abnormalities as multifactorial are their etiological heterogeneity (as a consequence of which their transmission patterns are inconsistent with Mendelian patterns of inheritance), the lack of knowledge of the genetic factors involved, and the nature of environmental factors. The concept that is emerging is that human developmental abnormalities may be treated as inborn errors in development or morphogenesis in obvious analogy with, and as an extension of, the classical concept of inborn errors of metabolism (Epstein 1995). Therefore, diverse dysmorphogenetic causes (including those “driven” by multigene deletions) can produce similar malformations.

OTHER POTENTIALLY RELEVANT DATA

Induction of Mutations at Expanded Simple Tandem Repeat Loci in the Mouse and Minisatellite Loci in Human Germ Cells

Introduction

Since the mid-1990s, several studies have been carried out on the induction of germ cell mutations at expanded simple tandem repeat (ESTR) loci in mice (formerly called minisatellites) and at minisatellite loci in humans. These are regions of the genome that do not code for any proteins but are highly unstable (mutable), both spontaneously and under the influence of radiation. These attributes have facilitated detection of increases in mutation rates at radiation doses and sample sizes substantially smaller than those used in conventional mutation studies with germ cells. Although these loci do not code for proteins and most spontaneous and radiation-induced mutational changes in them are not associated with adverse health effects, some limited evidence is suggestive of a possible role of minisatellites in human disease (reviewed in Bridges 2001). For example, there are data suggesting that minisatellites can affect transcription of the insulin gene (IDDM2) and HRAS1 genes (Trepicchio and Krontiris 1992; Kennedy and others 1995) Further, it has been found that certain polymorphisms of the minisatellite at the 5′-flanking region of the IDDM2 gene may be associated with predisposition to insulin-dependent diabetes mellitus (Bell and others 1984; Bennett and others 1995). Additionally, there is suggestive evidence of an association between the risk of cancer and mutations in the HRAS1 gene (Krontiris and others 1993; Phelan and others 1996). Although it is not possible at present to use data from these studies for radiation risk estimation, they are considered in this report because some of the findings have exposed interesting aspects of the radiation response at these loci that have parallelisms to the genomic instability phenomenon recorded in irradiated somatic cell systems and therefore relevant for ongoing debates in radiobiology. Most of these studies have been reviewed recently (Bridges 2001; UNSCEAR 2001). The principal conclusions are summarized here; and details are presented in Annex 4F.

Mouse Studies

Mutations at the ESTR loci can be induced by both low-and high-LET (neutrons from californium-252 [252Cf]) irradiation of mouse germ cells (Dubrova and others 1993, 1998a, 1998b, 2000a, 2000b; Sadamoto and others 1994; Fan and others 1995; Niwa and others 1996). For both types of radiations, the dose-effect relationship for mutations induced in spermatogonial stem cells is consistent with linearity. The high frequency of induced mutations strongly supports the view that they are unlikely to result from direct radiation damage to these small genomic loci themselves (i.e., they are nontargeted events arising indirectly as a result of genomic instability; Niwa and others 1996; Dubrova and others 1998b; Niwa and Kominami 2001). There is evidence that this instability is not the result of a general genome-wide increase in meiotic recombination rate (Barber and others 2000).

This genomic instability is transmissible to at least two generations resulting in increased frequencies of mutations (Dubrova and others 2000b; Barber and others 2002). These findings add further support to observations on genomic instability recorded in somatic cells—the occurrence of genetic changes in the progeny of irradiated cells at delayed times (in terms of cell generations) after irradiation.

Data on ESTR mutations obtained in experiments involving irradiated spermatogonial stem cells permit an estimate of the DD of about 0.33 Gy for acute X-irradiation, similar to that known for specific locus mutations in mice (Dubrova and others 1998b). It should be noted, however, that both the average spontaneous rate (0.111 per band) and the induction rate (0.338 Gy−1) are orders of magnitude higher than those of specific locus mutations.

There are some discrepancies between the findings of Dubrova and colleagues and those of Niwa and colleagues: (1) In the work of Dubrova and colleagues, post-meiotic germ cells are not sensitive to mutation induction at the ESTR loci, whereas in the work of Niwa and colleagues, all germ cells are sensitive, albeit to different degrees; it is not yet clear whether these differences are due to differences in the mouse strains used or to some other reasons. (2) In the work of Niwa and colleagues, F1 tests showed increased frequencies of mutations in the unirradiated maternal allele, suggesting the occurrence of destabilization in the zygote; however this occurs only after spermatozoal but not after gonial irradiation of the males; in the work of Dubrova and colleagues, the data imply that destabilization occurs in the F1 zygote when the spermatozoa used for fertilization received irradiation either at the postmeiotic or premeiotic stages in spite of observations that postmeiotic germ cells were not sensitive to mutation induction.



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