Techniques for assessment of teratogenic effects: developmental enzyme patterns

Most studies designed for assessing teratogenic effects focus on only three of four types of final manifestations of abnormal development; namely intrauterine death, malformations, and growth retardation. Developmental toxicity evaluations generally do not include functional deficits. Current techniques are inadequate for assessing functional capability during perinatal development, and there is a need for improved measures. Thus, measurement of developmental enzyme patterns is proposed as an approach that directly evaluates acquisition of metabolic competence of fundamental organ systems. During ontogenesis most organs acquire their full complement of enzyme activities in a programmed sequence which corresponds to attainment of complete functional capability. The usual alterations in enzyme activity that characterize these patterns occur at one of three time periods, namely, late fetal, early neonatal, or late suckling. Qualitative or quantitative changes in these patterns at any time by one or more key enzymes of a tissue could be indicative of developmental toxicity. Factors are outlined relating to consideration of developmental enzyme profiles as indices of maturation capable of reflecting the action of toxic agents. This presentation: (1) reviews the current state of the art for evaluating effects on development, (2) considers the applicability of enzyme patterns for biochemical assessment of development, (3) characterizes the target tissues and those metabolic pathways and/or specific enzymes most sensitive and adaptable to practical toxicity evaluations, and (4) describes the steps being taken to validate this system. The ultimate objective of this approach is to determine whether alterations in developmental enzyme profiles will provide a technique with improved capability for assessing developmental toxicity.