Abstracts

Rationale: A recent hypothesis proposing that estrogen imbalance underlies mechanisms involved in the etiology of epilepsy (Fucic et al., in press) has open new prospects for the diagnostics and therapy of this disease. This new, complex approach to diagnostics and treatment of epilepsy suggests that epilepsy is not just a neurological disease but a syndrome of reproductive and neurological disturbances. As such, it requires new biomarkers. We introduced a new genotoxicological biomarker, in vivo micronucleus (MN) assay, in order to evaluate possible genome damage in newborns transplacentally exposed to antineoplastic drugs (AED) in mother-newborn cohort. Methods: Our followed up study included pregnant women who were receiving (AED) with aromatase inhibitors as active substances. Using in vivo (MN) in mother-newborn pilot cohort study 30 matched control pairs and 15 pairs treated by AED were analysed. Investigation was approved by the Ethical Committee of Univ. Hosp. "Sisters of Mercy". All subjects included in study signed a written consent. Results: Significantlly (p<0.001) higher MN frequency was found in newborns transplacentally exposed to AED than in control newborns (2.75±0.9 and 1.79± 0.5 respectively). There was no signficant difference in MN frequency between treated and control mothers. Conclusions: One of the side effects of antiepileptic therapy by aromatase inhibitors are the elevated levels of testosterone. According to our hypothesis increased genome damage in newborns is caused by increased levels of testosterone, which is a known aneugen agent. The lack of detectible genome damage in mothers treated by AED, contrary to intrauterine exposed newborns, may be consequence of specific developmental susceptibility to increased testosterone levels during the prenatal life. Further research should tell whether the detected genome damage in newborn is of transient character. The etiology of epilepsy and some other neurological diseases seems to be related with the polymorphisms of aromatase and gene 15q21.1 as a potential candidate risk factor and biomarker. Additionally, as AEDs may increase intrauterine exposure of female foetus to testosterone, this may program polycystic ovary syndrome via the CYP 19 (TTTA)n alleles. To conclude, future monitoring of epilepsy patients should include the folowing biomarkers (a) MN frequency (b) single nucleotide polymorphisms coding aromatase region (such as rs2470152, TTTA) (c) endogenous aromatase inhibitor levels (d) child versus adult aromatase levels and (e) broad screening for estradiol/testosterone levels. These biomarkers could improve better monitoring and predicition of therapy results, and contribute to designing new therapy appraoches for epilepsy.Acknowledgment: Investigation was funded by the Croatian Ministry of Science, Education and Sport.