Mechanisms behind pyrethroid toxicity: involvement of epigenetic impairment in a progressive model of neurodegeneration induced by neonatal pesticide exposure.

Neonatal exposure to low dosage of permethrin (PERM) pesticide during brain development leads to the impairment of the dopaminergic system in rat striatum nucleus, promoting oxidative stress and behavioral changes associated, later in life, with the development of a progressive Parkinson's-like disease (PD). Previous studies demonstrated that PERM, a widely used pesticide suitable for pest control and anti-woodworm agent, is able to modulate DNA methyltransferases and -synuclein expression by NURR1 modulation in early life exposed rats. Data obtained in this work suggested that epigenetics could be a potential mechanism through which environmental factors interact with the genome by modulating gene expression. This hypothesis was supported by the evidence that the progressive PD could be developed in sensitive animals only if the exposure take place during the early window of epigenetic plasticity. This study aimed us to evaluate if PERM could modulate global DNA methylation and hydroxymethylation, as well as histone post-translational modifications, at specific gene loci in the early stages of disease progression. Moreover, in order to investigate PERM/Nurr1 and α-synuclein/NURR1 interactions, in silico studies were performed and compared with known Nurr1 agonists’ binding association and other biological data obtained in the rat model. Results show significant alteration in epigenetic regulatory mechanisms and dopamine-related gene expression. Additionally, we found that PERM competes for the same two binding sites of known NURR1 agonists, with a lower free energy of binding for PERM, suggesting a stable association of PERM with the orphan receptor. A strong affinity for NURR1 by synuclein was also identified. This study links the risk in the onset of a late neurodegeneration process with an early exposure to an environmental pesticide. The control of xenobiotic exposure during the epigenetic window of plasticity might be useful to preserve health in sensitive organisms.