Teratogen Screening: State of the Art


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PMID: 23408063 (PubMed) - PMCID: PMC3558154 - View online: PubReader
Volume 2, Issue 3, July-September , Page 115 to 121
Thursday, June 17, 2010 :Received , Monday, August 9, 2010 :Accepted


  • Corresponding author Julia Schumann, Ph.D., Institute of Physiological Chemistry, aculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany, Tel: +49-341-9738107 Fax: +49-341-9738119 E-mail: julia.schumann@vmf.uni-leipzig.de
    - Faculty of Veterinary Medicine, Institute of Physiological Chemistry, University of Leipzig , Leipzig, Germany

Abstract: Due to the number of new substances coming into use every year and the increasing amounts of chemicals, which are introduced into the environment, there is a high demand for a rapid, reliable and cost-effective method for detection of developmental toxicity. To meet this challenge various in vitro techniques have been established additional to in vivo animal testing. This review introduces the techniques in existence at the moment. Requirements on an ideal in vitro teratogenicity test system are stated, and the advantages and disadvantages of the present methods are discussed.

 

 


Introduction :
The need for efficient methods to screen new chemicals, drugs and environmental pollutants for their toxicity is obvious. However, from of the thousands of chemicals in commercial use, only a small fraction has been tested for their teratogenic activity so far (1). Moreover, the underlying mechanisms behind the developmental toxicity of compounds known to have a teratogenic potential has solely partially elucidated if any (1).
In context of pharmaceutically relevant substances the evaluation of the embryo toxic potential is of special importance. Very early in the course of the development of drugs a newly synthesized compound has to be tested for its acute and chronic as well as for its developmental toxicity. This preclinical evaluation of the long-term safety of a drug implies high throughput screenings of


possible cytotoxic, mutagenic, embryo toxic and teratogenic effects.
Due to the number of new substances coming into use every year and the increasing amounts of chemicals, which are introduced into the environment, there is a high demand for a rapid, reliable and cost-effective method for detection of developmental toxicity. This review introduces the techniques in existence at the moment. In this, in vitro systems are brought into the focus of attention. Requirements on an ideal in vitro teratogenicity test system are stated, and the advantages and disadvantages of the present methods are discussed.

Animal Test Systems
The preclinical evaluation of drugs traditionally involves large numbers of animals to predict possible drug side-effects.
Various animal-based test systems established for screening a potential teratogenic activity are conducted on pregnant laboratory animals, usually mammals such as mice, rats, rabbits and nonhuman primates. This way, the test compound is administered daily during the period of organogenesis of the fetus. Near-term the fetus is examined for skeletal, visceral and external anomalies (2,3).
Although this screening procedure has been of value especially until the eighties in the last century, however there are certain drawbacks to consider. Generally, the in vivo assays are very time consuming, laborious and expensive, thus contravening with the current need for rapid testing of potential drugs (2,3). Moreover, due to differences in maternal metabolism, transport and maternal-fetal membrane relationships animal studies often indicate substantial differences of toxicity between species. A compound that is demonstrably teratogenic in animals may not be so in man or vice versa (2,3).
To complicate the situation numerous additional factors as the nutritional state of the dam, the variability in the developmental age of embryos from litter to litter or within the same litter as well as placental functions must to be taken into account at interpretation of data (2,3). It can be stated, that pregnant animal testing alone is not qualified to predict the teratogenic potential of new compounds. Furthermore, there is an increased political and public demand to reduce the use of laboratory animals due to objections to experiments on living animals.

In vitro Techniques
Many of the variables of in vivo test systems e.g. species differences can be eliminated or at least controlled by in vitro techniques. Besides, in vitro tests are simple and cost-efficient. However, unlike other toxicity testing systems, in vitro analysis for teratogenicity presents certain special circumstances since the target in this case is a rapidly growing embryo, whose tissues are simultaneously embarked on divergent differentiation pathways. Thus, the test system has to be designed in a way that the in vitro data can be interpreted in terms of a possible in vivo outcome.
Main characteristics of an ideal in vitro teratogenicity screening system (Table 1) include its relevance to mechanisms of teratogenesis as well as the involvement of developmental events in addition to desirable features common to other

 



Table 1. Main characteristics of an ideal in vitro teratogenicity screening system adapted from Wilson (1978) [4]
Table 1. Main characteristics of an ideal in vitro teratogenicity screening system adapted from Wilson (1978) [4]




Table 2. Various parameters which may indicate teratogenic activity of a compound in whole embryo culture test systems adapted from Kochar (1980) [2]
Table 2. Various parameters which may indicate teratogenic activity of a compound in whole embryo culture test systems adapted from Kochar (1980) [2]




Table 3. Advantages and disadvantages of whole embryo culture test systems adapted from Fantel (1982) [3]
Table 3. Advantages and disadvantages of whole embryo culture test systems adapted from Fantel (1982) [3]





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