In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats.
The present work was designed to study the mechanisms associated with Nurr1 modulation following early life permethrin (PERM) treatment during rat's life span. Here we demonstrate that PERM exposure in rats, at a dose close to No Observed Adverse Effect Level (NOAEL) for 15days during neonatal brain development leads to its accumulation long after exposure. In striatum from adolescent rats we detected an increase in DNA methyltransferases (DNMTs) such as DNMT1, DNMT3a, Tyrosine hydroxylase, monomeric and aggregated α-synuclein protein levels. Adult rats showed enhanced DNMT3b and α-synuclein aggregation compared to the control group, while with aging a significant decrease in all biomarkers studied was observed. No changes in Nurr1 promoter methylation in adolescent, adult and old rats were found. In silico studies showed clear evidence of a strong binding interaction between PERM and its metabolite 3-phenoxybenzoic acid with the nuclear orphan receptor Nurr1. These findings suggest that an additional interference with the dopaminergic neuron pathway could occur in situ during PERM accumulation in brain. Therefore, Nurr1 modulation in early life PERM-treated rats, depends on age-related adaptive responses in animals.
School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
Donatella
D
Fedeli
School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
Maura
M
Montani
School of Advanced Studies, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
Laura
L
Bordoni
Department of Life and Environmental Sciences (DISVA), Marche Polytechnic University, Ancona, Italy.
Roberta
R
Galeazzi
School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
Cinzia
C
Nasuti
REQUIMTE, Instituto Superior de Engenharia do Porto, Instituto Politécnica do Porto, Rua Dr. António Bernardino de Almeida, 431, 4200-072 Porto, Portugal.
Luísa
L
Correia-Sá
REQUIMTE, Instituto Superior de Engenharia do Porto, Instituto Politécnica do Porto, Rua Dr. António Bernardino de Almeida, 431, 4200-072 Porto, Portugal.
Valentina F
VF
Domingues
Epigenetics and Developmental Biology Group, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India.
Maini
M
Jayant
Epigenetics and Developmental Biology Group, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India.
Vani
V
Brahmachari
Department of Life and Environmental Sciences (DISVA), Marche Polytechnic University, Ancona, Italy.
Luca
L
Massaccesi
Department of Life and Environmental Sciences (DISVA), Marche Polytechnic University, Ancona, Italy.
Emiliano
E
Laudadio
School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy. Electronic address: rosita.gabbianelli@unicam.it.
Rosita
R
Gabbianelli
D000375:Aging / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D026023:Permethrin / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D055503:Protein Multimerization; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000378:metabolism
D001565:Benzoates; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C497606:Snca protein, rat; D051844:alpha-Synuclein; D026023:Permethrin; C017618:3-phenoxybenzoic acid; D015254:DNA Modification Methylases
DNMTs; Nurr1 promoter methylation; early life permethrin exposure; molecular docking; rat; α-synuclein