In Vitro Testing of Lung Carcinogenicity for an In Silico-Identified Cluster of Mycotoxins (2024)

2023, Exposure and Health

Occurrence of emerging mycotoxins in food and feed is reported worldwide, but studies on their toxic effects are still limited. Our previous study based on in silico approaches has evidenced an association between some cyclic peptidic mycotoxins and non-small cell lung cancer. In this work, an in vitro toxicological investigation of these mycotoxins (enniatin A, enniatin B, beauvericin, apicidin and destruxin B) was performed. Several pathways involved in lung cancer pathology, as revealed by the KEGG pathway map, were tested on A549 and NCI-H226 human lung cells. Effects on viability, apoptosis, cell cycle, DNA damage, reactive oxygen species, and IL-8 secretion were determined after 24-h mycotoxin treatment at concentrations between 0.01 and 100 µM. Enniatin A, beauvericin and apicidin presented a similar response for all endpoints. Moreover, they were the most toxic compounds, with IC 50 around 2.2 and 13.1 µM, and apoptosis induction in both cell lines. Enniatin B did not induce a complete decrease in cell viability and did not provoke apoptosis. Destruxin B increased caspase 3 activity and altered cell cycle at concentrations above 6.25 µM in A549 cells, suggesting apoptosis activation, although it did not reduce cell viability in either cell line. Finally, enniatins A and B, apicidin, beauvericin and destruxin B increased the release of the pro-inflammatory IL-8. The in vitro results of this work confirmed the prediction using in silico approaches as some hallmarks of cancer can be observed after treatment of lung cells with this mycotoxin cluster. The toxic effects observed in human lung cells confirmed that the presence of these emerging mycotoxins in agricultural products, food and feed might be hazardous for human health and that a link with lung cancer was further outlined for three of them.

In vitro assessment of emerging mycotoxins co-occurring in cheese: a potential health hazard

Arch Toxicol, 2024

Some Penicillium strains used in cheese ripening produce emerging mycotoxins, notably roquefortine C (ROQC) and cyclopiazonic acid (CPA), as well as enniatins (ENNs) and beauvericin (BEA). Co-occurrence of these mycotoxins in natural samples has been reported worldwide, however, most studies focus on the toxicity of a single mycotoxin. In the present study, the effects of ROQC and CPA alone and in combination with BEA and ENNs A, A1, B, and B1 were analysed in human neuroblastoma cells. ROQC and CPA reduced cell viability, with IC 50 values of 49.5 and 7.3 µM, respectively, and induced caspase-8-mediated apoptosis. When ROQC and CPA were binary combined with ENNs, an enhancement of their individual effects was observed. Furthermore, a clear synergism was produced when ROQC and CPA were mixed with the four ENNs. An additive effect was also described for the combination of CPA + ENNs (A, A1, B, B1) + BEA. Finally, the effects of commercial cheese extracts containing the mentioned mycotoxins were evaluated, finding a strong reduction in cell viability. These results suggest that the co-occurrence of emerging mycotoxins in natural matrices could pose a potential health risk.

Beauvericin: The beauty and the beast

Environmental Toxicology and Pharmacology, 2020

Toxicity Predictions for Mycotoxins: A Combined In Silico Approach on Enniatin-Like Cluster

Exposure and Health, 2022

Due to climate change, mycotoxins are expected to become a specific concern worldwide. In the future, predicted changes in environmental conditions will affect the growth of crops and may favor the development of fungi and, therefore, the presence of mycotoxins. In addition to direct human oral exposure to mycotoxins through cereal food products, potential human exposure may also occur as a result of crop contamination with mycotoxins via animal feed and consumption of meat or milk products. Fungi can produce numerous compounds, many of which have not yet been characterized, including in terms of their toxicological potency. A large number of mycotoxins and their metabolites have not been evaluated for their toxicity so far. In this study, an innovative combined strategy based on several validated in silico tools was used to assess specific toxicity endpoints. From a list of 552 mycotoxins, 12 mycotoxins were clustered together based on physico-chemical parameters. On this specific cluster, firstly quantitative structure-activity relationship (QSAR) tools were used to assess the mutagenic and carcinogenic potential of each compound. From this analysis, 12 mycotoxins were found to have a potential activity in cancer promotion. The link between these compounds and cancer activity was further investigated by two complementary approaches: identification of gene pathways involved in the toxic response and a datamining search. Altogether, the results point to a potential association between these mycotoxins and lung cancer.

Interactions between ABC-transport proteins and the secondary Fusarium metabolites enniatin and beauvericin

2009

A Review of the Mycotoxin Enniatin B

Frontiers in public health, 2017

Mycotoxin enniatin B (ENN B) is a secondary metabolism product by Fusarium fungi. It is a well-known antibacterial, antihelmintic, antifungal, herbicidal, and insecticidal compound. It has been found as a contaminant in several food commodities, particularly in cereal grains, co-occurring also with other mycotoxins. The primary mechanism of action of ENN B is mainly due to its ionophoric characteristics, but the exact mechanism is still unclear. In the last two decades, it has been a topic of great interest since its potent mammalian cytotoxic activity was demonstrated in several mammalian cell lines. Moreover, the co-exposure in vitro with other mycotoxins enhances its toxic potential through synergic effects, depending on the concentrations tested. Despite its clear cytotoxic effect, European Food Safety Authority stated that acute exposure to ENNs, such as ENN B, does not indicate concern for human health, but a concern might be the chronic exposure. However, given the lack of re...

Transport of enniatin B and enniatin B1 across the blood-brain barrier and hints for neurotoxic effects in cerebral cells

PLOS ONE, 2018

Oxidative stress and DNA interactions are not involved in Enniatin- and Beauvericin-mediated apoptosis induction

Molecular Nutrition & Food Research, 2009

Assessing the Effect of Mycotoxin Combinations: Which Mathematical Model Is (the Most) Appropriate?

Toxins

In the past decades, many studies have examined the nature of the interaction between mycotoxins in biological models classifying interaction effects as antagonisms, additive effects, or synergisms based on a comparison of the observed effect with the expected effect of combination. Among several described mathematical models, the arithmetic definition of additivity and factorial analysis of variance were the most commonly used in mycotoxicology. These models are incorrectly based on the assumption that mycotoxin dose-effect curves are linear. More appropriate mathematical models for assessing mycotoxin interactions include Bliss independence, Loewe’s additivity law, combination index, and isobologram analysis, Chou-Talalays median-effect approach, response surface, code for the identification of synergism numerically efficient (CISNE) and MixLow method. However, it seems that neither model is ideal. This review discusses the advantages and disadvantages of these mathematical models.

Co-Occurrence of DON and Emerging Mycotoxins in Worldwide Finished Pig Feed and Their Combined Toxicity in Intestinal Cells

Toxins, 2019

Single and combined effects of regulated and emerging mycotoxins on viability and mitochondrial function of SH-SY5Y cells

Food and Chemical Toxicology, 2021