Current Pharmaceutical Design - Volume 7, Issue 9, 2001

The current review focuses on the malformations resulting from mutations in Pax3 and the interactions of Pax3 mutations with chemically induced teratogenesis, as well as other mutant genes or genetic strains, as a paradigm to illustrate the connections among genetics, protein function, and teratology. Splotch mice result from various mutations involving Pax3, and Waardenburg syndromes I and III in the human are due to mutations in PAX3. The human and murine phenotype/genotype correlations are thus compared and contrasted. The role of Pax3 in normal development, as well as the regulation of Pax3 expression and DNA binding, are also addressed on the premise that a mechanistic understanding of normal developmental processes is prerequisite to full comprehension of the mechanisms by which abnormal development is induced. Pax3 encodes a transcription factor involved in myogenesis, melanogenesis and neurogenesis, as well as regulating genes that may be involved in other cellular processes. The primary goal of this review is to examine the role of a single important developmental gene in the interaction of genetics and abnormal development.

Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (I Kr ), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block I Kr , in addition to its known blockade of sodium channels. Animal studies indicate that I Kr is expressed in the embryo and that the embryonic heart is extremely susceptible to I Kr -blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective I Kr -blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

Retinoids (vitamin A and its analogs) exert profound effects on a wide variety of life processes,

Many developmental toxicants and teratogens require prior metabolism to reactive species or free radicals to exert toxicity. Thus the knowledge of conceptal biotransformation is absolutely critical in understanding toxicity of these chemicals. Due to extremely low content of cytochrome P450 in the embryo and other conceptal tissues, the research focus in recent years has steadily shifted toward enzymes capable of peroxidative oxidation of xenobiotics. At least three enzymes viz. lipoxygenase, peroxidase and prostaglandin synthase, each capable of peroxidative xenobiotic metabolism, occur in conceptal tissues of man and laboratory animals in biologically significant amounts. This review mainly summarizes the available information on the enzymatic bioactivation of teratogens and developmental toxicants belonging to diverse classes such as drugs, pesticides, environmental contaminants, industrial and other chemicals. Additionally, some discussion is devoted toward issues such as drug-drug interactions. The emerging new information on the peroxidative glutathione conjugate formation from xenobiotics is also presented. A critical need for gathering more information on this subject using different enzyme preparations from human conceptal tissues is stressed to avoid tragedies in the future.

Increasing evidence points to the possible risks of delayed effects upon prenatal exposure to chemicals; the evaluation of such effects may pose serious problems to clinicians, epidemiologists and toxicologists. In fact, several systems (e.g., nervous, excretory) show important developmental processes well after the organogenetic period, up to the postnatal phase; accordingly, these are also expected to be sensitive targets of developmental toxicants, resulting in impairment of the function and/or functional reserve. This review describes the effects of several groups of drugs on the functional maturation and histogenesis of the kidney (e.g., aminoglycosides, angiotensin-converting enzyme inhibitors, indomethacin) and brain (e.g., anticonvulsivants, antiretroviral compounds, benzodiazepines) upon exposure in utero of humans and laboratory animals. The available data stress the importance for risk assessment of an adequate knowledge of both developmental biology and mechanisms of toxicity. The design of developmental toxicity studies should allow an evaluation of targets most relevant for a given drug (or group of drugs); moreover, the analysis of functional development should receive the due attention within the safety assessment of chemicals.