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Toxicogenomics applied to teratogenicity studies

: Hewitt, P.G.; Kramer, P.-J.; Borlak, J.


Borlak, J.:
Handbook of toxicogenomics : Strategies and applications
Weinheim: Wiley-VCH, 2005
ISBN: 3-527-30342-1
Book Article
Fraunhofer ITEM ()
Genetic toxicology; Genomics; Proteomics; Gene expression

Teratology is the study of birth defects – structural or functional abnormalities that are present at birth. In humans, most of the observed birth defects are caused by random genetic errors; however, some are caused by environmental factors. For a chemical to be labelled a teratogen it must significantly increase the occurrence of structural or functional abnormalities in offspring at a dose that does not cause severe toxicity in the mother. Adverse effects on development under these conditions maybe secondary to the stress on the maternal system. The malformations are dependent on two major factors; namely, exposure level and timing of exposure. It is also a common finding that foetuses react differently within the same womb. This is probably due to certain foetuses being exposed to higher concentrations of toxicant or to genetic variations in susceptibility.
Teratology, the study of 'monsters' (terata), was based originally only on observations and had perceived supernatural implications. The acceptance of the basic genetics concepts in the early 20th century provided a scientific basis for the cause of congenital defects. Very early in the 20th century scientists began to link environmental insults to birth defects [ for example, ionising radiation (Hipple and Pagenstrecher, 1907), sex hormones (Lillie, 1917), and chemicals (Gillman et al., 1948)]. The supposed safety of the human foetus was refuted as far back as 1941, after thousands of children exposed to German measles were born with cataracts, deafness, and congenital heart disease (Greg, 1941). This was confirmed by the thalidomide disaster in the late 1950s and early 1960s, which involved at least 12 000 children in 46 countries (McBride, 1961; Lenz, 1962; Colborn et al., 1996). This instance, in particular, prompted government intervention to assure appropriate testing of drugs and other xenobiotics in pregnant mammals. More recently (June 2000) it was reported that approximately 50% of all pregnancies in the U.S.A. result in prenatal or postnatal death or an otherwise less than healthy baby.
The term 'teratogenicity' has been largely replaced by the more general term developmental toxicology, to allow for more adverse developmental problems - and to takeinto account species differences. Developmental toxicity can be described as any structural or functional alteration, reversible or irreversible, caused by environmental insults, which interferes with homeostasis, normal growth, differentiation, development, and/or behaviour. The potential targets include the fertilized egg or zygote (prior to implantation and prior to formation of the three primary germ layers), the embryo during major organ development (organogenesis), the foetus in the post-embryonic period, and the neonate or postnatal offspring. In the developing foetus there is the necessity for very precise temporal and spatial sequencing of specific cell numbers and types for normal differentiation, including programmed cell death. In most animals, cells communicate via signalling pathways, which are repeatedly used in various combinations at different times and locations in the embryo and foetus. Chemical disruption of these pathways clearly leads to abnormal development of the foetus.
Teratogenicity testing is traditionally performed in test animals, which may respond differently from humans. Susceptibility to teratogenic effects shows extreme variability between different species, including responses to ACE inhibitors, aspirin, vitamin A, and thalidomide, which are negative in certain animal species (especially the rat) but which have been shown to be teratogenic in humans (Table 18.1). A comprehensive list of drugs and chemicals that are teratogenic are referenced in Schardein (1985). As a result of this discrepancy between animals and humans, there is a strong need for good (better) testing strategies. A better testing strategy is required, as a positive teratogenicity result in an animal model alone should not be a reason for halting drug development or lead to removal of the drug from the market. In other words, teratogenicity can be controlled in humans (i. e., do not prescribe to pregnant women) or be safely prescribed (for example, vitamin A and aspirin), as a low but pharmacologically active dose of such a compound may have beneficial effects but no teratogenicity at all.[...]