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22 pages, 7397 KiB

Open AccessArticle

Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats

by František Bárta, Alena Dedíková, Michaela Bebová, Šárka Dušková, Jaroslav Mráz, Heinz H. Schmeiser, Volker M. Arlt, Petr Hodek and Marie Stiborová

Int. J. Mol. Sci. 2021, 22(19), 10479; https://doi.org/10.3390/ijms221910479 - 28 Sep 2021

Cited by 17 | Viewed by 2847

Abstract

The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804–2818, 2020), [...] Read more.

The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804–2818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI/AAII mixture). Using the same rat model, we investigated how exposure to the AAI/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using ³²P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy. Full article

(This article belongs to the Special Issue Food Toxicants)

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15 pages, 9344 KiB

Open AccessArticle

Cereulide Exposure Caused Cytopathogenic Damages of Liver and Kidney in Mice

by Danyang Li, Ruqin Lin, Yangyang Xu, Qingmei Chen, Fengru Deng, Yiqun Deng and Jikai Wen

Int. J. Mol. Sci. 2021, 22(17), 9148; https://doi.org/10.3390/ijms22179148 - 24 Aug 2021

Cited by 5 | Viewed by 2712

Abstract

Cereulide is one of the main food-borne toxins for vomiting synthesized by Bacillus cereus, and it widely contaminates meat, eggs, milk, and starchy foods. However, the toxicological effects and mechanisms of the long-time exposure of cereulide in vivo remain unknown. In this [...] Read more.

Cereulide is one of the main food-borne toxins for vomiting synthesized by Bacillus cereus, and it widely contaminates meat, eggs, milk, and starchy foods. However, the toxicological effects and mechanisms of the long-time exposure of cereulide in vivo remain unknown. In this study, oral administration of 50 and 200 μg/kg body weight cereulide in the mice for 28 days caused oxidative stress in liver and kidney tissues and induce abnormal expression of inflammatory factors. In pathogenesis, cereulide exposure activated endoplasmic reticulum stress (ER stress) via the pathways of inositol-requiring enzyme 1α (IRE1α)/Xbox binding protein (XBP1) and PRKR-like ER kinase (PERK)/eukaryotic translation initiation factor 2α (eIF2α), and consequently led to the apoptosis and tissue damages in mouse liver and kidney. In vitro, we confirmed that the accumulation of reactive oxygen species (ROS) caused by cereulide is the main factor leading to ER stress in HepaRG and HEK293T cells. Supplementation of sodium butyrate (NaB) inhibited the activations of IRE1α/XBP1 and PERK/eIF2α pathways caused by cereulide exposure in mice, and reduced the cell apoptosis in liver and kidney. In conclusion, this study provides a new insight in understanding the toxicological mechanism and prevention of cereulide exposure. Full article

(This article belongs to the Special Issue Food Toxicants)

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19 pages, 3178 KiB

Open AccessArticle

Benzo[a]pyrene-Induced Genotoxicity in Rats Is Affected by Co-Exposure to Sudan I by Altering the Expression of Biotransformation Enzymes

by Helena Dračínská, Radek Indra, Sandra Jelínková, Věra Černá, Volker Manfred Arlt and Marie Stiborová

Int. J. Mol. Sci. 2021, 22(15), 8062; https://doi.org/10.3390/ijms22158062 - 28 Jul 2021

Cited by 11 | Viewed by 2818

Abstract

The environmental pollutant benzo[a]pyrene (BaP) is a human carcinogen that reacts with DNA after metabolic activation catalysed by cytochromes P450 (CYP) 1A1 and 1B1 together with microsomal epoxide hydrolase. The azo dye Sudan I is a potent inducer of CYP1A1/2. Here, [...] Read more.

The environmental pollutant benzo[a]pyrene (BaP) is a human carcinogen that reacts with DNA after metabolic activation catalysed by cytochromes P450 (CYP) 1A1 and 1B1 together with microsomal epoxide hydrolase. The azo dye Sudan I is a potent inducer of CYP1A1/2. Here, Wistar rats were either treated with single doses of BaP (150 mg/kg bw) or Sudan I (50 mg/kg bw) alone or with both compounds in combination to explore BaP-derived DNA adduct formation in vivo. Using ³²P-postlabelling, DNA adducts generated by BaP-7,8-dihydrodiol-9,10-epoxide were found in livers of rats treated with BaP alone or co-exposed to Sudan I. During co-exposure to Sudan I prior to BaP treatment, BaP-DNA adduct levels increased 2.1-fold in comparison to BaP treatment alone. Similarly, hepatic microsomes isolated from rats exposed to Sudan I prior to BaP treatment were also the most effective in generating DNA adducts in vitro with the activated metabolites BaP-7,8-dihydrodiol or BaP-9-ol as intermediates. DNA adduct formation correlated with changes in the expression and/or enzyme activities of CYP1A1, 1A2 and 1B1 in hepatic microsomes. Thus, BaP genotoxicity in rats in vivo appears to be related to the enhanced expression and/or activity of hepatic CYP1A1/2 and 1B1 caused by exposure of rats to the studied compounds. Our results indicate that the industrially employed azo dye Sudan I potentiates the genotoxicity of the human carcinogen BaP, and exposure to both substances at the same time seems to be hazardous to humans. Full article

(This article belongs to the Special Issue Food Toxicants)

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19 pages, 2577 KiB

Open AccessArticle

Determination of Two Differently Manufactured Silicon Dioxide Nanoparticles by Cloud Point Extraction Approach in Intestinal Cells, Intestinal Barriers and Tissues

by Na-Kyung Yoo, Ye-Rin Jeon and Soo-Jin Choi

Int. J. Mol. Sci. 2021, 22(13), 7035; https://doi.org/10.3390/ijms22137035 - 29 Jun 2021

Cited by 12 | Viewed by 3301

Abstract

Food additive amorphous silicon dioxide (SiO₂) particles are manufactured by two different methods—precipitated and fumed procedures—which can induce different physicochemical properties and biological fates. In this study, precipitated and fumed SiO₂ particles were characterized in terms of constituent particle size, [...] Read more.

Food additive amorphous silicon dioxide (SiO₂) particles are manufactured by two different methods—precipitated and fumed procedures—which can induce different physicochemical properties and biological fates. In this study, precipitated and fumed SiO₂ particles were characterized in terms of constituent particle size, hydrodynamic diameter, zeta potential, surface area, and solubility. Their fates in intestinal cells, intestinal barriers, and tissues after oral administration in rats were determined by optimizing Triton X-114-based cloud point extraction (CPE). The results demonstrate that the constituent particle sizes of precipitated and fumed SiO₂ particles were similar, but their aggregate states differed from biofluid types, which also affect dissolution properties. Significantly higher cellular uptake, intestinal transport amount, and tissue accumulation of precipitated SiO₂ than of fumed SiO₂ was found. The intracellular fates of both types of particles in intestinal cells were primarily particle forms, but slowly decomposed into ions during intestinal transport and after distribution in the liver, and completely dissolved in the bloodstream and kidneys. These findings will provide crucial information for understanding and predicting the potential toxicity of food additive SiO₂ after oral intake. Full article

(This article belongs to the Special Issue Food Toxicants)

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20 pages, 4971 KiB

Open AccessArticle

Particle Size and Biological Fate of ZnO Do Not Cause Acute Toxicity, but Affect Toxicokinetics and Gene Expression Profiles in the Rat Livers after Oral Administration

by Jin Yu and Soo-Jin Choi

Int. J. Mol. Sci. 2021, 22(4), 1698; https://doi.org/10.3390/ijms22041698 - 8 Feb 2021

Cited by 23 | Viewed by 2608

Abstract

Zinc oxide (ZnO) particles have been used as dietary supplements because zinc is an essential trace element for humans. Along with the rapid development of nanotechnology, the use of ZnO nanoparticles (NPs) is increasing in the food industry, but their oral toxicity potential [...] Read more.

Zinc oxide (ZnO) particles have been used as dietary supplements because zinc is an essential trace element for humans. Along with the rapid development of nanotechnology, the use of ZnO nanoparticles (NPs) is increasing in the food industry, but their oral toxicity potential still remains to be answered. In this study, the effects of particle size and biological fate of ZnO on acute toxicity, toxicokinetics, and gene expression profiles in the livers were investigated after oral administration of ZnO NPs (N-ZnO), bulk-sized ZnO (B-ZnO) or Zn ions in rats. The plasma concentration-time profiles after a single-dose oral administration of ZnOs differed depending on particle/ionic forms and particle size, showing high absorption of Zn ions, followed by N-ZnO and B-ZnO, although in vivo solubility did not differ from particle size. No significant acute toxicity was found after oral administration of ZnOs for 14 days in rats. However, transcriptomic responses in the livers were differently affected, showing that metabolic process and metal biding were up-regulated by Zn ions and N-ZnO, respectively, which were not pronounced in the liver treated with B-ZnO. These findings will be useful to predict the potential oral toxicity of ZnO NPs and further mechanistic and long-term exposure studies are required to assume their safety. Full article

(This article belongs to the Special Issue Food Toxicants)

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17 pages, 5018 KiB

Open AccessArticle

Polycyclic Aromatic Hydrocarbons Activate the Aryl Hydrocarbon Receptor and the Constitutive Androstane Receptor to Regulate Xenobiotic Metabolism in Human Liver Cells

by Lisa Goedtke, Heike Sprenger, Ute Hofmann, Felix F. Schmidt, Helen S. Hammer, Ulrich M. Zanger, Oliver Poetz, Albrecht Seidel, Albert Braeuning and Stefanie Hessel-Pras

Int. J. Mol. Sci. 2021, 22(1), 372; https://doi.org/10.3390/ijms22010372 - 31 Dec 2020

Cited by 33 | Viewed by 4034

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential. Full article

(This article belongs to the Special Issue Food Toxicants)

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18 pages, 3768 KiB

Open AccessArticle

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies

by Peramaiyan Rajendran, Rebai Ben Ammar, Fatma J. Al-Saeedi, Maged E. Mohamed, Medhat A. ElNaggar, Saeed Y. Al-Ramadan, Gamal M. Bekhet and Ahmed M. Soliman

Int. J. Mol. Sci. 2021, 22(1), 217; https://doi.org/10.3390/ijms22010217 - 28 Dec 2020

Cited by 83 | Viewed by 4925

Abstract

In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated [...] Read more.

In this study, kaempferol (KFL) shows hepatoprotective activity against zearalenone (ZEA)-induced oxidative stress and its underlying mechanisms in in vitro and in vivo models were investigated. Oxidative stress plays a critical role in the pathophysiology of various hepatic ailments and is normally regulated by reactive oxygen species (ROS). ZEA is a mycotoxin known to exert toxicity via inflammation and ROS accumulation. This study aims to explore the protective role of KFL against ZEA-triggered hepatic injury via the PI3K/Akt-regulated Nrf2 pathway. KFL augmented the phosphorylation of PI3K and Akt, which may stimulate antioxidative and antiapoptotic signaling in hepatic cells. KFL upregulated Nrf2 phosphorylation and the expression of antioxidant genes HO-1 and NQO-1 in a dose-dependent manner under ZEA-induced oxidative stress. Nrf2 knockdown via small-interfering RNA (siRNA) inhibited the KFL-mediated defence against ZEA-induced hepatotoxicity. In vivo studies showed that KFL decreased inflammation and lipid peroxidation and increased H₂O₂ scavenging and biochemical marker enzyme expression. KFL was able to normalize the expression of liver antioxidant enzymes SOD, CAT and GSH and showed a protective effect against ZEA-induced pathophysiology in the livers of mice. These outcomes demonstrate that KFL possesses notable hepatoprotective roles against ZEA-induced damage in vivo and in vitro. These protective properties of KFL may occur through the stimulation of Nrf2/HO-1 cascades and PI3K/Akt signaling. Full article

(This article belongs to the Special Issue Food Toxicants)

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12 pages, 2986 KiB

Open AccessArticle

Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner

by Josephin Glück, Julia Waizenegger, Albert Braeuning and Stefanie Hessel-Pras

Int. J. Mol. Sci. 2021, 22(1), 202; https://doi.org/10.3390/ijms22010202 - 28 Dec 2020

Cited by 19 | Viewed by 2304

Abstract

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of [...] Read more.

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure–activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment. Full article

(This article belongs to the Special Issue Food Toxicants)

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17 pages, 2160 KiB

Open AccessArticle

Effect of Acrylamide Supplementation on the Population of Vasoactive Intestinal Peptide (VIP)-Like Immunoreactive Neurons in the Porcine Small Intestine

by Katarzyna Palus, Michał Bulc and Jarosław Całka

Int. J. Mol. Sci. 2020, 21(24), 9691; https://doi.org/10.3390/ijms21249691 - 18 Dec 2020

Cited by 3 | Viewed by 2238

Abstract

Acrylamide is one of the harmful substances present in food. The present study aimed to establish the effect of acrylamide supplementation in tolerable daily intake (TDI) dose (0.5 µg/kg b.w./day) and a dose ten times higher than TDI (5 µg/kg b.w./day) on the [...] Read more.

Acrylamide is one of the harmful substances present in food. The present study aimed to establish the effect of acrylamide supplementation in tolerable daily intake (TDI) dose (0.5 µg/kg b.w./day) and a dose ten times higher than TDI (5 µg/kg b.w./day) on the population of vasoactive intestinal peptide-like immunoreactive (VIP-LI) neurons in the porcine small intestine and the degree of the co-localization of VIP with other neuroactive substances (neuronal nitric oxide synthase (nNOS), substance P (SP), and cocaine- and amphetamine-regulated transcript peptide (CART)). In our work, 15 Danish landrace gilts (5 in each experimental group) received capsules (empty or with low or high doses of acrylamide) for a period of 28 days with their morning feeding. Using double immunofluorescence staining, we established that acrylamide supplementation increased the number of neurons showing immunoreactivity towards VIP in all types of enteric nervous system (ENS) plexuses and fragments of the small intestine studied. Moreover, both doses of acrylamide led to changes in the degree of co-localization of VIP with nNOS, SP, and CART in intramural neurons. The observed changes may be the adaptation of neurons to local inflammation, oxidative stress, or the direct toxic effects of acrylamide on intestinal neurons, also referred to as neuronal plasticity. Full article

(This article belongs to the Special Issue Food Toxicants)

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30 pages, 813 KiB

Open AccessReview

Polycyclic Aromatic Hydrocarbons in Foods: Biological Effects, Legislation, Occurrence, Analytical Methods, and Strategies to Reduce Their Formation

by Geni Rodrigues Sampaio, Glória Maria Guizellini, Simone Alves da Silva, Adriana Palma de Almeida, Ana Clara C. Pinaffi-Langley, Marcelo Macedo Rogero, Adriano Costa de Camargo and Elizabeth A. F. S. Torres

Int. J. Mol. Sci. 2021, 22(11), 6010; https://doi.org/10.3390/ijms22116010 - 2 Jun 2021

Cited by 148 | Viewed by 13043

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds comprised of carbon and hydrogen molecules in a cyclic arrangement. PAHs are associated with risks to human health, especially carcinogenesis. One form of exposure to these compounds is through ingestion of contaminated food, which can occur [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds comprised of carbon and hydrogen molecules in a cyclic arrangement. PAHs are associated with risks to human health, especially carcinogenesis. One form of exposure to these compounds is through ingestion of contaminated food, which can occur during preparation and processing involving high temperatures (e.g., grilling, smoking, toasting, roasting, and frying) as well as through PAHs present in the soil, air, and water (i.e., environmental pollution). Differently from changes caused by microbiological characteristics and lipid oxidation, consumers cannot sensorially perceive PAH contamination in food products, thereby hindering their ability to reject these foods. Herein, the occurrence and biological effects of PAHs were comprehensively explored, as well as analytical methods to monitor their levels, legislations, and strategies to reduce their generation in food products. This review updates the current knowledge and addresses recent regulation changes concerning the widespread PAHs contamination in several types of food, often surpassing the concentration limits deemed acceptable by current legislations. Therefore, effective measures involving different food processing strategies are needed to prevent and reduce PAHs contamination, thereby decreasing human exposure and detrimental health effects. Furthermore, gaps in literature have been addressed to provide a basis for future studies. Full article

(This article belongs to the Special Issue Food Toxicants)

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