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

J 2021

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

SOUDERS, Christopher L., II, Anna RUSHIN, Christina L. SANCHEZ, Darby TOTH, Ondřej ADAMOVSKÝ et. al.

Základní údaje

Originální název

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

Autoři

SOUDERS, Christopher L., II (840 Spojené státy), Anna RUSHIN (840 Spojené státy), Christina L. SANCHEZ (840 Spojené státy), Darby TOTH (840 Spojené státy), Ondřej ADAMOVSKÝ (203 Česká republika, garant, domácí) a Christopher J. MARTYNIUK (840 Spojené státy)

Vydání

NEUROTOXICOLOGY, AMSTERDAM, ELSEVIER, 2021, 0161-813X

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30103 Neurosciences

Stát vydavatele

Nizozemské království

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.398

Kód RIV

RIV/00216224:14310/21:00122535

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1016/j.neuro.2021.05.011

UT WoS

000671176600006

Klíčová slova anglicky

Pesticides; Parkinson's disease; Mitochondrial bioenergetics; Apoptosis; Transcriptomics; Pathway analysis

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 10. 2021 21:40, Mgr. Michaela Hylsová, Ph.D.

Anotace

V originále

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.

Návaznosti

EF17_043/0009632, projekt VaV

Název: CETOCOEN Excellence

LM2018121, projekt VaV

Název: Výzkumná infrastruktura RECETOX (Akronym: RECETOX RI)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, RECETOX RI

857560, interní kód MU
(Kód CEP: EF17_043/0009632)

Název: CETOCOEN Excellence (Akronym: CETOCOEN Excellence)

Investor: Evropská unie, CETOCOEN Excellence, Spreading excellence and widening participation

Citovat

SOUDERS, Christopher L., II, Anna RUSHIN, Christina L. SANCHEZ, Darby TOTH, Ondřej ADAMOVSKÝ a Christopher J. MARTYNIUK. Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil. NEUROTOXICOLOGY. AMSTERDAM: ELSEVIER, 2021, roč. 85, July 2021, s. 173-185. ISSN 0161-813X. Dostupné z: https://dx.doi.org/10.1016/j.neuro.2021.05.011.

@article{1796218,
   author = {Souders, Christopher L., II and Rushin, Anna and Sanchez, Christina L. and Toth, Darby and Adamovský, Ondřej and Martyniuk, Christopher J.},
   article_location = {AMSTERDAM},
   article_number = {July 2021},
   doi = {http://dx.doi.org/10.1016/j.neuro.2021.05.011},
   keywords = {Pesticides; Parkinson's disease; Mitochondrial bioenergetics; Apoptosis; Transcriptomics; Pathway analysis},
   language = {eng},
   issn = {0161-813X},
   journal = {NEUROTOXICOLOGY},
   title = {Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil},
   url = {https://www.sciencedirect.com/science/article/pii/S0161813X21000565?via%3Dihub},
   volume = {85},
   year = {2021}
}

TY  - JOUR
ID  - 1796218
AU  - Souders, Christopher L., II - Rushin, Anna - Sanchez, Christina L. - Toth, Darby - Adamovský, Ondřej - Martyniuk, Christopher J.
PY  - 2021
TI  - Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil
JF  - NEUROTOXICOLOGY
VL  - 85
IS  - July 2021
SP  - 173-185
EP  - 173-185
PB  - ELSEVIER
SN  - 0161813X
KW  - Pesticides
KW  - Parkinson's disease
KW  - Mitochondrial bioenergetics
KW  - Apoptosis
KW  - Transcriptomics
KW  - Pathway analysis
UR  - https://www.sciencedirect.com/science/article/pii/S0161813X21000565?via%3Dihub
N2  - 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.
ER  -

SOUDERS, Christopher L., II, Anna RUSHIN, Christina L. SANCHEZ, Darby TOTH, Ondřej ADAMOVSKÝ a Christopher J. MARTYNIUK. Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil. \textit{NEUROTOXICOLOGY}. AMSTERDAM: ELSEVIER, 2021, roč.~85, July 2021, s.~173-185. ISSN~0161-813X. Dostupné z: https://dx.doi.org/10.1016/j.neuro.2021.05.011.

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