Postnatal Exposure Sensitizes for Zinc/Paraquat-Induced Neuronal Apoptosis, Adulthood Exposure Leads to the Final Effects

Abstract

Developmental exposure to zinc/paraquat (Zn/PQ) increases susceptibility to dopaminergic neurodegeneration caused by adulthood exposure to Zn/PQ in rodents through augmented oxidative stress and inflammation. The current study delved into the consequences of developmental Zn/PQ exposure on the mechanism of neuronal apoptosis induced by Zn/PQ exposure in adult animals. Postnatal Zn/PQ exposure augmented the loss of dopaminergic neurons and mitochondrial reactive oxygen species production in animals that received Zn/PQ re-exposure at adult stage. A more pronounced decline was observed in mitochondrial complex I/III activity and membrane potential in animals that encountered both postnatal and adult stage exposures to Zn/PQ than in the animals exposed during adult stage only. Developmental Zn/PQ exposure noticeably enhanced apoptotic neuronal cell death in the animals who received adulthood re-exposure, as evident by the higher mitochondrial cytochrome c efflux into cytosol and reduction in procaspase-3 levels compared to the animals that encountered with Zn/PQ during adulthood alone. Whilst Zn exposure during adulthood pointed towards activation of Bax-mediated apoptotic cell death, exposure to PQ at adult stage suggested involvement of Bak-mediated apoptotic cell death irrespective of developmental exposure to PQ or Zn. The study indicated that early life exposure renders the dopaminergic neurons more susceptible to Zn/PQ-induced mitochondria-mediated apoptotic neuronal cell death following subsequent toxic insult in adult life. However, final apoptotic disposal pathway for dopaminergic neurons seems to be directed by the toxic insult encountered in adulthood.