Epigenetics of pesticide-induced neurodegeneration

Early life represents a key window of plasticity important for the programming of development through the cellular differentiation. During this period exogenous and endogenous factors (ie, nutrition, xenobiotics, stress, hypoxia, infections, hormones, etc.) can induce epigenetic changes leading to the development of diseases in adult age. Transgenerational studies on animal models show that epigenetic changes, such as DNA methylation and histone modifications, may be transferred to next generations. Early life exposure to permethrin pyrethroid pesticide, during brain development is associated with dopaminergic neuron degeneration leading to the Parkinson-like disease (PD) in an animal model [1-3]. Pyrethroids represent a real risk for population as demonstrated by the detection of pyrethroid metabolites in the urine of world wide population, depending on the their presence in all vegetables and fruits [4-6]. Data from the PD animal model demonstrated that genetic and epigenetic changes are associated to permethrin-induced neurodegeneration [7]. Nurr1, the transcription factor responsible for the development and the maintenance of dopaminergic neurons, was significantly increased in early-life permethrin exposed rats. 33% of their untreated offspring showed the same Nurr1 increase as their parents. Furthermore, both mothers and untreated offspring (F1 generation) demonstrated a decrease in global DNA methylation. It should be underlined that permethrin can cross the blood brain barrier, storing in the brain after the end of treatment. Furthermore, several sites of binding between Nurr1 and permethrin have been identified by in silico studies highlighting that the direct interaction between permethrin and Nurr1 might be suggested in early-life exposed rats [1]. Epigenetic modifications have been hypothesized to explain the intergenerational effect of Nurr1 in F1 generation. References [1] Fedeli D, Montani M, Bordoni L, Galeazzi R, Nasuti C, Correia-Sá L, Domingues VF, Jayant M, Brahmachari V, Massaccesi L, Laudadio E, Gabbianelli R. In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats. Neuroscience. 2017, 340, 411. [2] Nasuti C, Brunori G, Eusepi P, Marinelli L, Ciccocioppo R, Gabbianelli R.Early life exposure to permethrin: a progressive animal model of Parkinson's disease. J Pharmacol Toxicol Methods. 2017, 83, 80. [3] Carloni M, Nasuti C, Fedeli D, Montani M, Vadhana MS, Amici A, Gabbianelli R. Early life permethrin exposure induces long-term brain changes in Nurr1, NF-kB and Nrf-2. Brain Res. 2013, 17, 1515. [4] Marsha K. Morgan. Children’s Exposures to Pyrethroid Insecticides at Home: A Review of Data Collected in Published Exposure Measurement Studies Conducted in the United States. Int J Environ Res Public Health. 2012, 9, 296. [5] Dana Boyd Barr, Anders O. Olsson, Lee-Yang Wong, Simeon Udunka, Samuel E. Baker, Ralph D. Whitehead, Jr., Melina S. Magsumbol, Bryan L. Williams, Larry L. Needham. Urinary Concentrations of Metabolites of Pyrethroid Insecticides in the General U.S. Population: National Health and Nutrition Examination Survey 1999–2002. Environ Health Perspect. 2010, 118, 742. [6] W. Li, M.K. Morgan, S.E. Graham, J.M. Starr. Measurement of pyrethroids and their environmental degradation products in fresh fruits and vegetables using a modification of the quick easy cheap effective rugged safe (QuEChERS) method. Talanta 2016, 151, 42. [7] Bordoni L, Nasuti C, Mirto M, Caradonna F and Gabbianelli R. Intergenerational effect of early life exposure to permethrin: changes in global DNA methylation and in Nurr1 gene expression. Toxics, 2015, 3(4), 451.