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Mycotoxins, ochratoxin A (OTA), and citrinin (CTN) are toxic metabolites of filamentous fungi. The most common fungal species that produce OTA and CTN belong to genera Aspergillus, Penicillium, Fusarium, and Monascus, and these fungal species are found to be contaminant a wide range of grains, food, and food product. The aim of our study was to evaluate the sub-acute repeated dose oral toxicity of OTA and CTN in experimental rodents by following OECD test guidelines for testing chemicals no. 407 with minor modifications. Twenty-five rats of each sex were divided equally into five groups; vehicle control, OTA 25 μg/kg b. wt., OTA 100 μg/kg b. wt., CTN 25 μg/kg b.wt. and CTN 100 μg/kg b. wt. The results of this study showed no abnormal clinical signs during 28 days of the experimental period. We did not found any significant changes in body weight gain, food consumption pattern, organ weight, hematology except few parameters, and biochemical values in any of the treatment and control groups. However, histopathological observations revealed severe nephrotoxicity and mild follicular depletion in the spleen of 100 μg/kg b. wt. treated groups of both OTA and CTN mycotoxins. The findings of our study are of its first kind that reports the systemic toxicity of OTA and CTN oral exposure to laboratory rodents. • OTA and CTN were nephrotoxic and spleenotoxic at a dose of 100 μg/kg. • No statistically significant changed in body weight gain, food intake, and organ weight in any of the treated animals. • No clinic-pathological changes except a few parameters at 100 μg/kg group animals. • In 28 days of subacute toxicity, the NOAEL of OTA and CTN for rats is 25 μg/kg. [ABSTRACT FROM AUTHOR]

4-Methylbenzylidene camphor (4-MBC) is a widely used organic UV filter in personal care products. Extensive use of 4-MBC and its frequent detection in aquatic ecosystems defile the biota with muscular and neuronal impairments. This study investigates the neurobehavioral toxicity of 4-MBC using Danio rerio as a model organism. Embryos were exposed semi-statically to 4-MBC at 5, 50, and 500 μg/L concentrations for 10-day post fertilization (dpf). Embryos exhibited a significant thigmotaxis and decreased startle touch response with altered expression of nervous system mRNA transcripts on 5 & 10 dpf. Compared to the sham-exposed group, 4-MBC treated larvae exhibited changes in the expression of shha, ngn1, mbp, elavl3, α1-tubulin, syn2a, and gap43 genes. Since ngn1 induction is mediated by shh signaling during sensory neuron specification, the elevated protein expression of NGN1 indicates 4-MBC interference in the sonic hedgehog signaling pathway. This leads to sensory neuron impairment and function such as 'sense' as evident from reduced touch response. In addition, larval brain histology with a reduced number of cells in the Purkinje layer emblazing the defunct motor coordination. Predictive toxicity study also showed a higher affinity of 4-MBC to modeled Shh protein. Thus, the findings of the present work highlighted that 4-MBC is potential to induce developmental neurotoxicity at both behavioral and molecular functional perspectives, and developing D. rerio larvae could be considered as a suitable alternate animal model to assess the neurological dysfunction of organic UV filters. • 4-Methylbenzylidene (4-MBC) camphor alters D. rerio motor behavior. • Decreased touch response due to motor function deficit. • Brain histology reveals loss of neuronal cell population. • Altered expression of neurodevelopmental mRNA transcripts. • Docking studies confirm 4-MBC affinity and modulation with Sonic Hedgehog protein. [ABSTRACT FROM AUTHOR]

Abstract Patulin (PAT), a mycotoxin, is a natural contaminant that is produced by certain species of Penicillium, Aspergillus and Byssochlamys. The major contamination of PAT is in apple and apple based products. PAT is known to cause glutathione depletion, oxidative DNA damage and cell proliferation. Recently, in vitro studies have indicated that PAT can also increase the intestinal epithelial permeability, modulate tight junctions and decrease transepithelial electrical resistance. Nonetheless, no previous study has evaluated the mechanisms responsible for PAT-induced intestinal toxicity or its relevance to the in vivo situation. Here, Wistar rats were orally treated with 100 μg/kg body weight (b.wt.) of PAT, either alone or along with 100 mg/kg b. wt. of celecoxib for 3 days. We found that PAT exposure led to significantly higher levels of PGE 2 in serum and intestinal tissue and high expression of COX-2 and Ki-67 compared to controls. Interestingly, our results showed that celecoxib treatment could decrease the PAT-induced PGE 2 and reduce the PAT-induced intestinal damage. To study the mechanistic aspect, normal rat intestinal epithelial cells (IEC-6) were treated with non-toxic concentrations (100 nM, 250 nM and 500 nM) of PAT for 6 h. It was observed that PAT exposure caused enhanced proliferation, higher expression of COX-2, and EP2 and EP4 receptors, along with increased PGE 2 secretion. Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3β and stabilizes β-catenin. Overall, our study suggests that the COX-2/EP2-EP4/β-catenin signaling cascades are involved in the regulation of PAT-induced intestinal cell proliferation and inflammation. Graphical abstract Unlabelled Image Highlights • Patulin exposure causes intestinal cell proliferation and inflammation. • Patulin causes over-expression of COX-2 and PGE 2 secretion. • EP2 and EP4 receptors are involved in the induction of COX-2 and PGE 2 secretion. • PGE 2 /EP2-EP4/β-catenin signaling regulates patulin induced intestinal toxicity. [ABSTRACT FROM AUTHOR]

Patulin (PAT) is a mycotoxin that contaminates a variety of food and foodstuffs. Earlier in vitro and in vivo findings have indicated that kidney is one of the target organs for PAT-induced toxicity. However, no study has evaluated the chronic effects of PAT exposure at environmentally relevant doses or elucidated the detailed mechanism(s) involved. Here, using in vitro and in vivo experimental approaches, we delineated the mechanism/s involved in pro-fibrotic changes in the kidney after low-dose chronic exposure to PAT. We found that non-toxic concentrations (50 nM and 100 nM) of PAT to normal rat kidney cells (NRK52E) caused a higher generation of reactive oxygen species (ROS) (mainly hydroxyl (•OH), peroxynitrite (ONOO−), and hypochlorite radical (ClO−). PAT exposure caused the activation of mitogen-activated protein kinases (MAPKs) and its downstream c-Jun/Fos signaling pathways. Moreover, our chromatin immunoprecipitation (ChIP) analysis suggested that c-Jun/Fos binds to the promoter region of Transforming growth factor beta (TGF-β 1) and possibly induces its expression. Results showed that PAT-induced TGF-β 1 further activates the TGF-β 1 /smad signaling pathways. Higher activation of slug and snail transcription factors further modulates the regulation of pro-fibrotic molecules. Similarly , in vivo results showed that PAT exposure to rats through gavage at 25 and 100 μg/kg b. wt had higher levels of kidney injury/toxicity markers namely vascular endothelial growth factor (VEGF), kidney Injury Molecule-1 (Kim-1), tissue inhibitor of metalloproteinase-1 (Timp-1), and clusterin (CLU). Additionally, histopathological analysis indicated significant alterations in renal tubules and glomeruli along with collagen deposition in PAT-treated rat kidneys. Overall, our data provide evidence of the involvement of ROS mediated MAPKs and TGF-β 1 /smad pathways in PAT-induced pro-fibrotic changes in the kidney via modulation of slug and snail expression. [Display omitted] • Low-dose chronic exposure to PAT caused pro-fibrotic changes in rat kidney. • Non-toxic concentrations of PAT caused activation of MAPKs and c-jun/c-fos. • Pharmacological inhibitor of JNK reduced the PAT-induced TGF-β expression. • Pharmacological inhibitor of TGF-β inhibited the PAT-induced EMT markers. • TGF-β/Smad pathway regulate pro-fibrotic changes via slug and snail expression. [ABSTRACT FROM AUTHOR]