Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Disruption of VEGFR Signaling Leading to Developmental Defects||AO||[[Aop:43#Essentiality of the Key Events|]]|
Level of Biological Organization
How this Key Event works
The risks for chemical effects on the reproductive cycle are broadly defined in two categories for regulatory purposes: reproductive (fertility, parturition, lactation) and developmental (mortality, malformations, growth and functional deficits). With respect to apical endpoints for developmental defects, the International Conference on Harmonization regulatory guidelines for embryo-fetal developmental toxicity testing (ICH 2005) require studies in both a rodent and a non-rodent species, usually rat and rabbit. The current paradigm was developed in response to the pandemic of phocomelia associated with maternal exposure to thalidomide during early pregnancy [Schardein 2000]; however, dose ranges of thalidomide that were teratogenic in the rabbit induced embryo-fetal loss in the rat [Janer et al. 2008]. This observation is consistent with current knowledge that the specificity of the manifestations of embryo-fetal toxicity may vary greatly between species, and even between strains within the same species [Hurtt et al. 2003; Janer et al. 2008; Knudsen et al. 2009; Rorije et al. 2012; Theunissen et al. 2016]. Recent advances in our knowledge of the molecular and cellular bases of embryogenesis serve to provide a deeper understanding of the fundamental developmental mechanisms that underlie Wilson's Principles of Teratology as the standard formulation of the basic tenets of the field [Friedman 2010].
AO1001 consolidates into one, the four main types of developmental defects observed in regulatory guideline studies (prenatal loss, malformations, low birth weight, and postnatal function). Any or all of these developmental defects may occur within the same litter or study. Congenital malformations refer to alterations in normal development that result from intrinsic (genetically programmed) or extrinsic (environmentally induced) perturbations of development. Mechanistically, some pathways may lead to specific types of malformations; however, a fundamental principle is that all four types of endpoints are important for hazard assessment. This is because even a simple MIE may disrupt the embryo in multiple ways that depend on the nature of the insult and timing of exposure.
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Developmental defects are typically assessed by observational studies of animal models and by human epidemiological studies. For animal models, the apical endpoints typically derive from a litter-based evaluation of fetuses just prior to birth or beyond. A study design fit for the purpose of regulatory toxicology adheres to regulatory guidelines specified by OECD Test Guideline No. 414 (Prenatal Developmental Toxicity Study). Prenatal animal studies in mammalian species where exposure to a drug or chemical is administered to the dam describe the occurrence and severity of effects to the mother and fetuses and perform statistical evaluations on a litter basis since the dam is the exposure unit. Latent effects that do not manifest at term, or are not reliably diagnosed until postnatal development or subsequent generations, may be detected by OECD Test No. 415 (One-Generation Reproduction Toxicity Study) or Test No. 416 (Two-Generation Reproduction Toxicity).
Evidence Supporting Taxonomic Applicability
Wilson's Principles of Teratology (circa 1977) support the taxonomic applicability of AO1001. According to these long-standing Wilson's principles, the first on "Susceptibility to Teratogenesis Depends on the Genotype of the Conceptus and a Manner in which this Interacts with Adverse Environmental Factors". This principle has four main tenets:
i) species differences account for the fact that certain species respond to particular teratogens where others do not, or at least not to the same extent (e.g., humans and other primates are vulnerable to thalidomide induced phocomelia whereas rodents are not);
ii) strain and intralitter differences account for the fact that some lineages of the same species with different genetic backgrounds can differ in teratogenic susceptibility;
iii) gene-environment interplay results in different patterns of abnormalities between organisms with the same genome raised in different environments, and between organisms with different genomes raised in the same environment; and
iv) multifactorial causation accounts for the complex interactions involving more than one gene and/or more than one environmental factor.
Friedman JM. The principles of teratology: are they still true? Birth Defects Res A. 2010 Oct;88(10):766-8. doi: 10.1002/bdra.20697.
Janer G, Slob W, Hakkert BC, Vermeire T and Piersma AH. A retrospective analysis of developmental toxicity studies in rat and rabbit: what is the added value of the rabbit as an additional test species? Regul Toxicol Pharmacol. 2008 50: 206-217.
Hurtt ME, Cappon GD and Browning A. Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food-producing animals. Food Chem Toxicol. 2003 41: 611-619.
Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ and Singh AV. Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA's ToxRefDB. Reprod Toxicol. 2009 28: 209-219.
Rorije E, van Hienen FJ, Dang ZC, Hakkert BH, Vermeire T and Piersma AH. Relative parameter sensitivity in prenatal toxicity studies with substances classified as developmental toxicants. Reprod Toxicol. 2012 34: 284-290.
Schardein J. Chemically Induced Birth Defects. 2000. New York, Marcel Decker Inc.
Theunissen PT, Beken S, Beyer BK, Breslin WJ, Cappon GD, Chen C, Chmielewski G, De Schaepdrijver L, Enright B, Foreman JE, Harrouk W, Hew KW, Hoberman AM, Hui JY, Knudsen TB, Laffan SB, Makris S, Martin M, McNerney ME, Siezen CL, Stanislaus DJ, Stewart J, Thompson KE, Tornesi B, Weinbauer G, Wood S, Van der Laan JW and Piersma AH. Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects. Chem Rev Toxicol. 2016 (in revision).