Rashkivska I. Neurotoxic effect of zeta-cypermethrin on rats under conditions of its influence in pre- and postnatal periods

Usage of different synthetic pyrethroids (SP) compounds in agriculture, industry and household is increasing every year in worldwide and Ukraine. SP are the fourth generation of insecticides that have replaced carbamates, organophosphorus and organochlorine compounds. Zeta-cypermethrin according to the chemical structure belongs to the second type of SP. Due to wide use of this type, their both direct and indirect effects constitute a significant threat to humans and animals. Fetal nervous system is one of the most vulnerable to the effects of various chemical compounds, including pyrethroid compounds insecticides, during ontogeny periods. The epidemiological data demonstrate that children who were exposed to pesticides, including the SP, during the prenatal and early postnatal developmental periods, subsequently suffered from various neurological disorders. These neurological disorders include autism spectrum disorders, changes in behavioral reactions, attention deficit hyperactivity disorder, learning disabilities disorders and different emotional problems. The dissertation is devoted to the study of the neurotoxic effects of zeta-cypermethrin on the nervous system of the offspring. Female rats were exposed to the test substance from day 6 of gestation to day 21 of lactation in doses of 0; 5; 12,5; 35 and 70 mg/kg/bw. Studies were performed on 58 pregnant and lactating female Wistar Hannover rats and their offspring. Studies were conducted in accordance with OECD guideline 426 (Developmental Neurotoxicity Study) and GLP requirements. During the course of the dissertation research, international methodological approaches to the study of neurotoxic effects of pesticides on the developing organism in accordance with OECD guideline 426 were introduced into the laboratory practice for the first time. Basis of the analysis of the obtained results, it was shown that zeta-cypermethrin at dose of 70 mg/kg bw coused maternal toxicity of females Р0 generation. Zeta-cypermethrin at doses of 35 mg/kg/bw and 70 mg/kg/bw causes a retardation in physical and sexual development of F1 offspring and affected the functional state of the nervous system of rats in the lactation period in terms of the rate of motor reflex formation and behavioral reactions. It was represented that sexual differences in sensitivity to the action of zeta-cypermethrin on the offspring were observed in the postnatal period: males were more sensitive than females. The selective age sensitivity to the general toxic effect of zeta-cypermethrin was established: The F1 offspring during the lactation period were more sensitive than the pregnant and lactating female rats. In order to assess the systemic toxicity and neurotoxicity of zeta-cypermethrin and cypermethrin, comparative studies of the effect of cypermethrin on pregnant and lactating female rats and on the functional state of the nervous system of their offspring under identical experimental conditions were conducted. Zeta-cypermethrin demonstrated more expressive general toxic and neurotoxic effects comparing with cypermethrin. According to the obtained results, the no-observed-effect-level (NOEL) for the neurotoxic effect of zeta-cypermethrin for offspring has been scientifically justified for the first time. NOEL for offspring female rats was 35 mg/kg/bw and for the male rats - 12,5 mg/kg/bw. The recommendation, whenever possible, is not to use synthetic pyrethroid-based agents indoor if pregnant women and children are present, so it will allow them to avoid the effects of these agents on the body and minimize its effects on the fetus and the newborn.