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Beauvericin (BEA) and enniatin B (ENNB)-induced impairment of mitochondria and lysosomes - potential sources of intracellular reactive iron triggering ferroptosis in Atlantic salmon primary hepatocytes

ABSTRACT: Beauvericin (BEA) and enniatin B (ENNB) are emerging mycotoxins frequently detected in plant-based fish feed. With ionophoric properties, they have shown cytotoxic potential in mammalian models. Sensitivity in fish is still largely unknown. Primary hepatocytes isolated from Atlantic salmon (Salmo salar) were used as a model and exposed to BEA and ENNB (0.05 – 10 µM) for 48 hours. Microscopy, evaluation of cell viability, total ATP, total H2O2, total iron content, total Gpx enzyme activity, and RNA sequencing were used to characterize the toxicodynamics of BEA and ENNB. Both mycotoxins became cytotoxic at ≥ 5 µM, causing condensation of the hepatocytes followed by formation of blister-like protrusions on the cell's membrane. RNA sequencing analysis at sub-cytotoxic levels indicated BEA and ENNB exposed hepatocytes to experience increased energy expenditure, elevated oxidative stress, and iron homeostasis disturbances sensitizing the hepatocytes to ferroptosis. The present study provides valuable knowledge disclosing the toxic action of these mycotoxins in Atlantic salmon primary hepatocytes.

ORGANISM(S): Salmo salar

PROVIDER: GSE193374 | GEO | 2022/01/17

REPOSITORIES: GEO

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Project description:The aquaculture industry has confronted severe economic losses due to infectious diseases in the last years. Piscirickettsiosis or Salmonid Rickettsial Septicaemia (SRS) is the bacterial disease caused by Piscirickettsia salmonis. This Gram-negative, non-motile, cellular pathogen has the ability to infect, survive, replicate, and propagate in salmonid monocytes/macrophages generating a systemic infection characterized by the colonization of several organs including kidney, liver, spleen, intestine, brain, ovary and gills. In this study, we attempted to determine whether global gene expression differences can be detected in different genetic groups of Atlantic salmon as a result of Piscirickettsia salmonis infection. Moreover, we sought to characterize the fish transcriptional response in order to reveal the mechanisms that might confer resistance in Atlantic salmon to an infection with Piscirickettsia salmonis. In doing so, after challenging with Piscirickettsia salmonis, we selected the families with the highest (HS) and the lowest (LS) recorded susceptibility for gene expression analysis using 32K cGRASP microarrays. Our results revealed in LS families expression changes are linked to iron depletion, as well as, low contents of iron in kidney cells and low bacterial load, indicated that the iron-withholding strategy of innate immunity is part of the mechanism of resistance against Piscirickettsia salmonis. This information contributes to elucidate the underlying mechanisms of resistance to Piscirickettsia salmonis infection in Atlantic salmon and to identify new candidate genes for selective breeding programmes. Forty full-sibling families of Atlantic salmon (Salmo salar) were infected by intraperitoneal injection with 0.2 mL Piscirickettsia salmonis (PS889, isolated from Oncorhynchus kisutch, 1M-CM-^W104 PFU/mL). After forty days, the fishes were harvested and the cumulative mortality (dead fish / total fish) for each family was calculated. For the second challenge, the six families with the highest cumulative mortality levels were considered of relatively high susceptibility (HS) and the six families with the lowest cumulative mortality levels were considered of relatively low susceptibility (LS) to the infection. Five control and five infected fish from three HS and three LS families were analyzed. For each HS and LS family, pools of RNA from control and infected fish were prepared separately and were reverse transcribed. Four slides were for each used family hybridized including two dye-swaped slides. Labeled samples were hybridized on a 32K cDNA microarray, developed at the Consortium for Genomics Research on All Salmonids Project (cGRASP), GEO accession number: GPL8904.

Project description:Infectious diseases among fish present an important economic burden for the aquaculture and fisheries industries around the world. For example, the infectious salmon anemia virus (ISAV) is known to infect farmed Atlantic salmon (Salmo salar), and results in millions of dollars of lost revenue to salmon farmers. Although improved management and husbandry practices over the last few years have minimized the losses and the number of outbreaks, the risk of new virulent isolates emerging is still a looming threat to the viability and sustainability of this industry. An understanding of the host-pathogen interactions at the molecular level during the course of an infection thus remains of strategic importance for the development of molecular tools and efficient vaccines capable of minimizing losses in the eventual case of a new outbreak. Using a 32 k cDNA microarray platform (cGRASP), we have studied various signaling pathways and immune regulated genes, activated or repressed, in Atlantic salmon head-kidney during the course of an ISAV infection. Gene expressions were measured at 5 different time-points: 6h, 24h, 3d, 7d and 16d post infection to get an overall view of changes as they occurred in time. The earliest time points showed only a few differentially expressed genes in infected fish, relative to controls, although as time progressed, many additional genes involved in key defense pathways were up-regulated including MHC type I, beta-2 microglobulin, TRIM 25 and CC-chemokine 19. During the latest stage of the infection process, many genes related to oxygen transportation were under-expressed, which correlates well with the anemia observed prior to death in Atlantic salmon infected with virulent strains of ISAV. Atlantic salmon smolts from 2 families of Atlantic salmon were IP injected with either 0.1mL of 10e5 TCID50 mL-1 of virus or 0.1mL of sham solution (L15 culture medium) and divided equally in four 1000 L tanks: 2 duplicate tanks containing ISAV injected fish and 2 duplicate control tanks containing sham solution injected fish. Four fish per family were sampled immediately prior to injection. An additional two fish per family per tank (four fish per family total) were sampled at 6h, 24h, 3d, 7d and 16d post injection. Head-kidney was dissected from each fish and used for microarray analysis. ISAV infected Atlantic salmon were compared to non-infected Atlantic salmon for each time-point.

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Beauvericin (BEA) and enniatin B (ENNB)-induced impairment of mitochondria and lysosomes - potential sources of intracellular reactive iron triggering ferroptosis in Atlantic salmon primary hepatocytes

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