•Fipronil sulfone metabolite was more cytotoxic than fipronil in SH-SY5Y cells.•Fipronil and fipronil sulfone induced NO and MDA production in SH-SY5Y cells.•Antioxidant compounds ameliorated ...fipronil and fipronil sulfone cytotoxicity.
Fipronil is a broad spectrum insecticide from the phenyl pyrazole family, which targets GABA receptor. Limited information is available about the metabolite fipronil sulfone cytotoxic actions. This study examined in vitro neurotoxicity of fipronil and fipronil sulfone and evaluated Trolox (vitamin E analog) (0.3, 1μM), N-acetyl-cysteine (0.5, 1mM), melatonin (0.1, 1μM) and Tempol (superoxide dismutase analog) (0.3, 0.5mM) protective role in SH-SY5Y cells. MTT and LDH assays were carried out to assess the cytotoxicity of fipronil and fipronil sulfone at 3–100μM concentrations. Fipronil sulfone was more toxic than fipronil. Tempol showed the best neuroprotectant profile against fipronil (50 and 150μM) and fipronil sulfone (3 and 10μM) reaching control levels. Fipronil (100μM) and fipronil sulfone (3μM) treatments induced a 4.7- and 5-fold increases in lipid peroxides measured as malondialdehyde (MDA) and a 2.2- and 2.0-fold increases in the levels of nitric oxide (NO). These results suggest that oxidative stress observed may be one of the major mechanisms of fipronil-induced neurotoxicity and it may be attributed in part to fipronil disposition and metabolism. Our results led us postulate that metabolite fipronil sulfone might be responsible for the fipronil-induced toxicity rather than fipronil itself.
Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform ...based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos.
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•Naive rat PSCs robustly contribute to live rat-mouse chimeras•A versatile CRISPR-Cas9 mediated interspecies blastocyst complementation system•Naive rodent PSCs show no chimeric contribution to post-implantation pig embryos•Chimerism is observed with some human iPSCs in post-implantation pig embryos
Human pluripotent stem cells robustly engraft into both cattle and pig pre-implantation blastocysts, but show limited chimeric contribution to post-implantation pig embryos.
The toxicokinetics of glyphosate after single 100
mg
kg
−1 intravenous (i.v.) and 400
mg
kg
−1 oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. ...Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration–time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (
T
1/2β) from plasma were 9.99
h after i.v. and 14.38
h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995
l
h
−1
kg
−1. After i.v. administration, the apparent volume of distribution in the second compartment (
V
2) and volume of distribution at steady state (
V
ss) were 2.39 and 2.99
l
kg
−1, respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a
T
max of 5.16
h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416
μg
ml
−1, respectively. The maximum plasma concentration of AMPA was achieved at 2.42
h. For AMPA, the elimination half-life (
T
1/2β) was 15.08
h after oral administration of glyphosate parent compound.
OBJECTIVE: XXXto assess the effect on cognition of a controlled intervention testing Mediterranean diets (MedDiet). DESIGN: XXXrandomized trial after 6.5 years of nutritional intervention. SETTING: ...Eight primary care centers affiliated to the University of Navarra. PARTICIPANTS: A random subsample of 285 participants (95 randomly allocated to each of 3 groups) of the PREDIMED-NAVARRA trial. All of them were at high vascular risk (44.8% men, 74.1± 5.7 years at cognitive evaluation). INTERVENTIONS: Nutritional intervention comparing two MedDiets (supplemented with extra-virgin olive oil EVOO or mixed nuts) versus a low-fat control diet. Participants received intensive education to increase adherence to the intended intervention. Participants allocated to the MedDiet groups received EVOO (1 l/week) or 30 g/day of mixed nuts. Dietary habits were evaluated using a validated 137-item food frequency questionnaire (FFQ). Additionally, adherence to MedDiet was appraised using a 14-item questionnaire both at baseline and yearly thereafter. MEASUREMENTS: XXXcognitive performance as a main outcome and cognitive status (normal, mild cognitive impairment MCI or dementia) as a secondary outcome were evaluated by two neurologists blinded to group assignment after 6.5 years of nutritional intervention. RESULTS: Better post-trial cognitive performance versus control in all cognitive domains and significantly better performance across fluency and memory tasks were observed for participants allocated to the MedDiet+EVOO group. After adjustment for sex, age, education, apolipoprotein E genotype, family history of cognitive impairment/dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia, diabetes, alcohol and total energy intake, this group also showed lower MCI (OR=0.34 95% CI: 0.12–0.97) compared with control group. Participants assigned to MedDiet+Nuts group did not differ from controls. CONCLUSION: A long-term intervention with an EVOO-rich MedDiet resulted in a better cognitive function in comparison with a control diet. However, non-significant differences were found for most cognitive domains. Participants allocated to an EVOO-rich MedDiet had less MCI than controls.
Despite the widespread use of pyrethroid insecticides that led to common exposure in the population, few studies have been conducted to quantitatively assess dose-additive effects of pyrethroids ...using a funcional measure involved in the common toxic mode of action. The aim of this study was to evaluate the potency and efficacy of 6 Type II pyretroids (α-cypermethrin, cyfluthrin, λ-cyhalothrin, deltamethrin, cyphenothrin and esfenvalerate) to evoke induction of both nitric oxide and lipid peroxides levels measured as malondialdehyde in three in vitro models (SH-SY5Y, HepG2 and Caco-2 human cells) as well as to test the hypothesis of dose additivity for mixtures of these same 6 pyrethroids. Concentration–responses for 6 pyrethroids were determined as well as the response to mixtures of all 6 pyrethroids. Additivity was tested assuming a dose-additive model. The human neuroblastoma SH-SY5Y cell line was the most sensitive in vitro model. The rank order of potency for cell SH-SY5Y viability MTT assay was deltamethrin>cyphenothrin>λ-cyhalothrin>cyfluthrin>esfenvalerate>α-cypermethrin. When 6 pyrethroids were present in the mixture at an equitoxic mixing ratio, the action on nitric oxide (NO) and lipid peroxides measured as malondialdehyde (MDA) production was consistent with a dose-additive model. The results of the present study are consistent with previous reports of additivity of pyrethroids in vivo e in vitro.
•Six Type II pyrethroids caused cytotoxicity in three human cell lines.•SH-SY5Y cell line was the most sensitive to type II pyrethroids and mixtures.•Type II pyrethroids and mixtures induced NO and MDA production.•Additivity was tested assuming a dose-additive model.•Dose addition predicted pyrethroid mixtures effects on NO and MDA production.
The effects of cyfluthrin oral exposure (1, 5, 10 and 20mg/kg bw, 6 days) on brain region monoamine levels of male rats were examined. Cyfluthrin-treated rats (1, 5 and 10mg/kg bw, orally 6 days), ...had no visible injury, i.e., no clinical signs of dysfunction were observed. However, rats treated with cyfluthrin at the highest dose (20mg/kg bw, orally 6 days) showed skeletal muscle contraction in the hind limbs, slight movement incoordination without any signs of dyskinesia and tremor after 1–2h of treatment. These signs were reversible at 6h after dose. After last dose of cyfluthrin, dopamine (DA) and serotonin (5-HT) and its metabolites levels were determined in brain regions hypothalamus, midbrain, hippocampus, striatum and prefrontal cortex by HPLC. Cyfluthrin (1mg/kg bw, orally 6 days) did not affect the DA, 5-HT and metabolites levels in the brain regions studied. Cyfluthrin (5, 10 and 20mg/kg bw, orally 6 days) caused a statistically significant decrease in DA and its metabolites DOPAC and HVA levels and in 5-HT and its metabolite 5-HIAA levels in a brain region- and dose-related manner. Moreover, cyfluthrin (20mg/kg bw, orally 6 days) evoked a statistically significant increase in 5-HT turnover in striatum and midbrain, and in DA turnover in striatum and prefrontal cortex. These findings indicate that serotoninergic and dopaminergic neurotransmission is affected by exposure to cyfluthrin and may contribute to the overall spectrum of neurotoxicity caused by this pyrethroid.
•Cyfluthrin oral exposure caused neurotoxicity in male rats.•Cyfluthrin altered the serotoninergic and dopaminergic neurotransmission.•Cyfluthrin caused a loss of DA and 5-HT and its metabolites levels in brain regions.•These data contribute to understand the mode of action of the toxicity of cyfluthrin.
Fipronil induces CYP isoforms in rats Caballero, M.V.; Ares, I.; Martínez, M. ...
Food and chemical toxicology,
September 2015, 2015-Sep, 2015-09-00, 20150901, Volume:
83
Journal Article
Peer reviewed
The goal of the present study was to evaluate fipronil effects on the activities of drug metabolizing enzymes in rat liver microsomes. Rats were orally treated with fipronil at doses of 1, 5, 10 and ...15 mg/kg bw/day for 6 days. Determinations of cytochrome P450 (CYP) enzyme activities were carried out in hepatic microsomes isolated from treated rats. The activities of some members of CYP2E, CYP1A, CYP2A, CYP2B and CYP3A subfamilies significantly increased after fipronil treatment in a dose-dependent manner as compared to control. The major effects were observed in the O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin (reflecting CYP1A1/2 activities), in the O-depenthylation of pentoxyresorufin and 16β-hydroxylation of testosterone (reflecting CYP2B1/2 activities), and in the N-demethylation of erythromycin and 6β-hydroxylation of testosterone (reflecting CYP3A1/2 activities). Immunoblot studies revealed that fipronil increased the apoprotein levels of CYP1A1. Our results suggest that fipronil is an inducer of hepatic phase I CYP enzymes, causing an increased potential to interact with a wide range of xenobiotics or endogenous chemicals that are substrates of the CYP1A, CYP2B and CYP3A subfamilies. Further investigations are required to in vivo evaluate the potential of the metabolite fipronil sulfone as an inducer of phase I CYP enzymes.
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•Male Wistar rats were orally treated with fipronil.•Repeated oral doses of 1, 5, 10 and 15 mg/kg bw/day, for six days, were tested.•Fipronil affected cytochrome P450 (CYP) enzyme activities in rat liver microsomes.•Fipronil increased CYP2E1, CYP1A1/2, CYP2A1, CYP2B1/2 and CYP3A1/2 enzyme activities.
The microstructure characteristics as well as the mechanical properties of an Inconel 625 alloy obtained by three processes: forging, SLM and LMD, are investigated. For the last two processes, known ...as “additive manufacturing”, the influence of printing parameters is considered as well as the role of possible heat treatments. First, microstructural analyses (SEM and EBSD) underline the presence of columnar dendrites with a very heterogeneous grain size for additive manufactured as-built materials. The microstructures appear highly textured, particularly for SLM ones which are also often finer than the ones obtained by LMD. Heat treatments and particularly a 1h-1100C∘ annealing is proven to improve the printed parts microstructure and to avoid a drastic decrease in terms of ductility, particularly for LMD parts. The LMD process with controlled laser power, coupled with appropriate heat treatment, finally produces materials with both microstructures and tensile mechanical properties close to or better than those of the wrought alloy.
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