Pyrethroid insecticides induce oxidative stress, immuno and neuro-toxicity in Wistar rats

Pyrethroids (Cypermethrin CY, Permethrin PERM, etc.) are widely used insecticides of low acute toxicity in mammals, however there are serious concerns on the risks related to their exposure. They mainly act on central nervous system and show significant effects on peripheral nerves, muscles and immune system. In this work, the effects of CY and/or PERM exposure on pup (1/10 LD50, 10 days) and adolescent (1/10 LD50, 60 days) rats were investigated. In particular the implications of pyrethroids exposure on immune and central nervous system were studied. Pyrethroids impair both monocytes and PMNs respiratory burst. They reduce reactive oxygen species production in activated monocytes while increase their level in PMNs. In vivo antioxidant supplementation (Vitamin E and/or Coenzyme Q10) can protect against the abnormal respiratory burst observed in PMNs from adolescent rats. In vivo and in vitro studies suggest physico-chemical changes at plasma membrane level in leukocytes. Moreover, pyrethroids induce protein and lipid oxidation in white blood cells. These insecticides increase protein oxidation also in striatum where PERM depletes GSH (both in pups and adolescent rats). In vivo Vitamin E supplementation restores the GSH level to the control value observed in adolescent rats. Moreover, antioxidant supplementation protects striata from the PERM induced DNA damage. PERM induces single and double-strand breaks as shown by comet assay. Modified versions of comet assay were performed in order to better characterize PERM induced DNA damage. With the aim to evaluate the role of mitochondrial superoxide anion on DNA damage, in vitro studies on striatal sub-mitochondrial particles (SMPs) were performed. In our experimental conditions, PERM inhibits mitochondrial complex I activity. This effect discards the involvement of mitochondria reactive oxygen species in the striatum DNA damage, while focalizes the main role of PERM on other oxidative stress pathways. The pivotal role of oxidative stress in PERM induced damage is underscored by the fact that in vitro GSH supplementation or pre-treatment prevents PERM induced DNA damage.