Early-Life Exposure to Permethrin Food Contaminant Inducing Neurodegeneration: Is It Matter of Epigenetics?

Early-Life Exposure to Permethrin Food Contaminant Inducing Neurodegeneration: Is It Matter of Epigenetics? Laura Bordoni1, Cinzia Nasuti2, Donatella Fedeli2, Rosita Gabbianelli2 1School of Advanced Studied and 2School of Pharmacy, University of Camerino, Italy Permethrin (PERM) exposure in rats at a dose close to No Observed Adverse Effect Level (NOAEL) for 15 days during neonatal brain development leads to the accumulation of the pesticide long after exposure and to the impairment of dopaminergic system in striatum nucleus, contributing later in life to the burden of oxidative stress and behavioral changes linked to a Parkinson’s like syndrome through several pathways. Among these, epigenetics is a strong candidate mechanism to be involved because of its well-known capability to modulate the effect that environmental factors have on the genome. Previous studies showed alteration of DNMT’s expression regulation and global DNA methylation both in the exposed and in F1 generation. Anyway the dynamic of the epigenetic contribution to the pathology onset is still not clear. In order to clarify the role of epigenetics in this Parkinson-like syndrome induced by a food contaminant, rats were gavaged through intragastric tube with PERM solubilized in corn oil at a dose of 1/50 of LD50 corresponding to 34.05 mg/kg. The compound was administered daily in the morning from PND6 to PND21 and control group was administered with vehicle. Animals where than sacrificed at 60PND and the expression of genes involved in the dopaminergic pathway, also related in Parkinson onset (Nurr1, TH, α-syn), and genes that regulate epigenetic mechanisms specifically in the brain (Mecp2, TET1, TET2, TET3) was analyzed. Global DNA methylation level assessed by ELISA and histone modifications at specific gene loci investigated through ChIP were also determined in order to clarify the epigenetic landscape. Significant alteration in terms of these markers has been identified in our model, suggesting that epigenetics can exert a pivotal role in the onset of this disease. This study focus on an emerging role of food intake, specifically in early-life, in the regulation of the onset later in life of chronic diseases through intriguing mechanisms such as epigenetics.