Comparison of long-term versus short-term effects of okadaic acid on the apoptotic status of human HepaRG cells

Dietrich, Jessica; Schindler, Magdalena; Lampen, Alfonso; Braeuning, Albert; Hessel-Pras, Stefanie

doi:10.1016/j.cbi.2020.108937

Cited by 10 publications

(6 citation statements)

References 39 publications

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“…on the order of one to two weeks may resolve false negative results. Encouragingly, in previous studies hepatotoxicity was effectively characterized in HepaRG cells after up to 14 days of chemical exposure(Donato et al ., 2022; Dietrich et al ., 2020; Anthérieu et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

Chemical screening of food-related chemicals for human fatty liver risk: Combining high content imaging of cellular responses with in vitro to in vivo extrapolation

Müller

Stamou

Englert

et al. 2022

Preprint

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Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent human disease with accumulating evidence linking its pathophysiology and co-morbidities to chemical exposures. The complex pathophysiology of NAFLD has limited the elucidation of potential chemical etiologies. In this study we generated a high-content imaging analysis method for the simultaneous quantification of sentinel steatosis cellular markers in chemically exposed human liver cells in vitro combined with a computational model for the extrapolation of human oral equivalent doses (OED). First, the in vitro test method was generated using 14 reference chemicals with known capacities to induce cellular alterations in nuclear morphology, lipid accumulation, mitochondrial membrane potential and oxidative stress. These effects were quantified on a single cell- and population-level, and then, using physiologically based pharmacokinetic modelling and reverse dosimetry, OEDs were extrapolated from these in vitro data. The extrapolated OEDs were confirmed to be within biologically relevant exposure ranges for the reference chemicals. Next, we tested 14 chemicals found in food, selected from thousands of putative chemicals on the basis of structure-based prediction for nuclear receptor activation. Amongst these, orotic acid had an extrapolated OED overlapping with realistic exposure ranges. By the strategy developed in this study, we were able to characterize known NAFLD-inducing chemicals and translate to data scarce food-related chemicals, amongst which we identified orotic acid to induce steatosis. This strategy addresses needs of next generation risk assessment, and can be used as a first chemical prioritization hazard screening step in a tiered approach to identify chemical risk factors for NAFLD.

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Section: Discussionmentioning

confidence: 99%

Chemical screening of food-related chemicals for human fatty liver risk: Combining high content imaging of cellular responses with in vitro to in vivo extrapolation

Müller

Stamou

Englert

et al. 2022

Preprint

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“…Our results showed that karlotoxins produced by Karlodinium veneficum (strain K10) induced apoptosis in the range of sublethal concentrations. Apoptosis has been described as a toxic effect triggered by microalgae toxins such as okadaic acid (Dietrich et al 2020), azaspiracids (Ferreiro et al 2017), or cyanotoxins (e.g., microcystin (Zeng et al 2014)). Recent studies on cyanotoxins showed that microcystin-LR induced apoptosis by activation of endoplasmic reticulum stress (Qi et al 2016).…”

Section: Embryotoxicity Of K Veneficum Supernatantmentioning

confidence: 99%

Sublethal effect of the toxic dinoflagellate Karlodinium veneficum on early life stages of zebrafish (Danio rerio)

Llanos-Rivera

Álvarez-Muñoz

Astuya-Villalón

et al. 2022

Environ Sci Pollut Res

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Dinoflagellates of the genus Karlodinium are ichthyotoxic species that produce toxins including karlotoxins and karmitoxins. Karlotoxins show hemolytic and cytotoxic activities and have been associated with fish mortality. This study evaluated the effect of toxins released into the environment of Karlodinium veneficum strain K10 (Ebro Delta, NW Mediterranean) on the early stages of Danio rerio (zebrafish). Extracts of the supernatant of K10 contained the mono-sulfated KmTx-10, KmTx-11, KmTx-12, KmTx-13, and a di-sulfated form of KmTx-10. Total egg mortality was observed for karlotoxin concentration higher than 2.69 μg L −1 . For 1.35 μg L −1 , 87% of development anomalies were evidenced (all concentrations were expressed as KmTx-2 equivalent). Larvae of 8 days postfertilization exposed to 1.35 µg L −1 presented epithelial damage with 80% of cells in the early apoptotic stage. Our results indicate that supernatants with low concentration of KmTxs produce both lethal and sublethal effects in early fish stages. Moreover, apoptosis was induced at concentrations as low as 0.01 μg L −1 . This is of great relevance since detrimental long-term effects due to exposure to low concentrations of these substances could affect wild and cultured fish.

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“…Studies show that OA has a variety of toxic effects, including cytotoxicity, carcinogenicity, neurotoxicity, as well as embryotoxicity [1,8]. OA is able to induce cell apoptosis in multiple human cell lines, such as TR14, NT2-N and SHSY5Y cells [9,10], malignant glioma cells [11], and HepaRG cells [12]. Interestingly, the nervous system is reported to be more sensitive to OA than other systems, though OA was not considered as a classical neurotoxin previously [9].…”

Section: Introductionmentioning

confidence: 99%

Okadaic Acid Exposure Induced Neural Tube Defects in Chicken (Gallus gallus) Embryos

Jiao

Wang

et al. 2021

Marine Drugs

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Okadaic acid (OA) is an important liposoluble shellfish toxin distributed worldwide, and is mainly responsible for diarrheic shellfish poisoning in human beings. It has a variety of toxicities, including cytotoxicity, embryonic toxicity, neurotoxicity, and even genotoxicity. However, there is no direct evidence of its developmental toxicity in human offspring. In this study, using the chicken (Gallus gallus) embryo as the animal model, we investigated the effects of OA exposure on neurogenesis and the incidence of neural tube defects (NTDs). We found that OA exposure could cause NTDs and inhibit the neuronal differentiation. Immunofluorescent staining of pHI3 and c-Caspase3 demonstrated that OA exposure could promote cell proliferation and inhibit cell apoptosis on the developing neural tube. Besides, the down-regulation of Nrf2 and increase in reactive oxygen species (ROS) content and superoxide dismutase (SOD) activity in the OA-exposed chicken embryos indicated that OA could result in oxidative stress in early chick embryos, which might enhance the risk of the subsequent NTDs. The inhibition of bone morphogenetic protein 4 (BMP4) and Sonic hedgehog (Shh) expression in the dorsal neural tube suggested that OA could also affect the formation of dorsolateral hinge points, which might ultimately hinder the closure of the neural tube. Transcriptome and qPCR analysis showed the expression of lipopolysaccharide-binding protein (LBP), transcription factor AP-1 (JUN), proto-oncogene protein c-fos (FOS), and C-C motif chemokine 4 (CCL4) in the Toll-like receptor signaling pathway was significantly increased in the OA-exposed embryos, suggesting that the NTDs induced by OA might be associated with the Toll-like receptor signaling pathway. Taken together, our findings could advance the understanding of the embryo–fetal developmental toxicity of OA on human gestation.

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Comparison of long-term versus short-term effects of okadaic acid on the apoptotic status of human HepaRG cells

Cited by 10 publications

References 39 publications

Chemical screening of food-related chemicals for human fatty liver risk: Combining high content imaging of cellular responses with in vitro to in vivo extrapolation

Chemical screening of food-related chemicals for human fatty liver risk: Combining high content imaging of cellular responses with in vitro to in vivo extrapolation

Sublethal effect of the toxic dinoflagellate Karlodinium veneficum on early life stages of zebrafish (Danio rerio)

Okadaic Acid Exposure Induced Neural Tube Defects in Chicken (Gallus gallus) Embryos

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