Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F21%3A00122535" target="_blank" >RIV/00216224:14310/21:00122535 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0161813X21000565?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0161813X21000565?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.neuro.2021.05.011" target="_blank" >10.1016/j.neuro.2021.05.011</a>

Result language

angličtina

Original language name

Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil

Original language description

The phenylpyrazole fipronil is an insecticide that inhibits gamma-amino-butyric acid (GABA) ionotropic receptors in the central nervous system. Experimental evidence suggests that fipronil acts as a neurotoxin and it is implicated in neurodegenerative diseases; however, the mechanisms of neurotoxicity are not fully elucidated. The objective of this study was to quantify mechanisms of fipronil-induced neurotoxicity in dopamine cells. Rat primary immortalized mesencephalic dopaminergic cells (N27) were treated with fipronil (0.25 up to 500 mu M depending on the assay). We measured endpoints related to mitochondrial bioenergetics, mitophagy, mitochondrial membrane potential, and ATP production in addition to discerning transcriptome responses to the pesticide. Fipronil reduced cell viability at 500 mu M after 24 h exposure and caspase 3/7 activity was significant increased after 6 and 12 h by 250 and 500 mu M fipronil. Subsequent endpoints were thus assessed at concentrations that were below cytotoxicity. We measured oxidative respiration of N27 cells following a 24 h exposure to one dose of either 0.25, 2.5, 25, or 50 mu M fipronil. Oxygen consumption rates (OCR) were not different between vehicle-control and 0.25 or 2.5 mu M fipronil treatments, but there was a similar to 40-60 % reduction in basal respiration, as well as reduced oligomycin-induced ATP production at 50 mu M. The reduction in OCR is hypothesized to be related to lower mitochondrial mass due to mitophagy. Mitochondrial membrane potential was also sensitive to fipronil, and it was compromised at concentrations of 2.5 mu M and above. To further elucidate the mechanisms linked to neurotoxicity, we conducted transcriptomics in dopamine cells following treatment with 25 mu M fipronil. Fipronil suppressed transcriptional networks associated with mitochondria (damage, depolarization, permeability, and fission), consistent with its effects on mitochondrial membrane potential. Altered gene networks also included those related to Alzheimer disease, inflammatory disease, nerve fiber degeneration, and neurofibrillary tangles. This study clarifies molecular targets of fipronil-induced neurotoxicity and supports, through multiple lines of evidence, that fipronil acts as a mitochondrial toxicant in dopamine cells. This is relevant to neurodegenerative diseases like Parkinson's disease as exposure to fipronil is associated with the progressive loss of nigrostriatal dopaminergic neurons in rodents.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

NEUROTOXICOLOGY

ISSN

0161-813X

e-ISSN

—

Volume of the periodical

85

Issue of the periodical within the volume

July 2021

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

13

Pages from-to

173-185

UT code for WoS article

000671176600006

EID of the result in the Scopus database

2-s2.0-85108148985