Neuroimmune consequences of teratological insult induced by cyclophosphamide exposure during intrauterine life in mice

A wide spectrum of the teratogenic effects of cyclophosphamide (CP) have been reported involving multiple tissues and organ systems of animals, but more population based studies may still be essential to conclusively demonstrate teratogenicity of CP in humans. However, a number of studies demonstrate that CP is a human teratogen due to its effects such as intrauterine growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, abnormal and small ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, cranial anomalies, preaxial upper limb and post-axial lower limb defects consisting of hypoplastic thumbs, and oligodactyly like bilateral absence of 4th and 5th toes [1]. Tissue distribution of CP is wide. The drug can cross placenta, found in breast milk and ascitic fluid. Moreover, it is remarkable to note that CP and its metabolites can cross blood brain barrier. This may be particularly important in relation to the fact that CNS anomalities are the foremost among the malformations induced by the drug. Investigations provide evidences implicating CP induced cell death as a common event in the pathogenesis associated with tissues destined to be malformed [2]. Although the importance of this cell death is recognized, little information is available concerning the biochemistry of teratogen-induced cell death. Teratogen-induced cell death is also selective, i.e. some cells within a tissue die while others survive. In addition, cells within some tissues die when exposed to CP while other cells are relatively resistant to the CP induced cell death [2]. The spectrum of teratogenic effects produced by cyclophosphamide in various species shows a striking similarity. Cyclophosphamide exposure leads to multiple central nervous systems (CNS) anomalies, the mode of neuronal damage need to be established and we have chosen murine system for our study. We also intend to investigate the teratological insult caused by cyclophosphamide on murine fetal thymuses. Since some preliminary studies have indicated the involvement of nervous system in cylophosphamide induced immune disorders [3], neuroimmunological consequences of cyclophosphamide exposure need to be explored.