Food and Chemical Toxicology最新文献

Dibutyltin dichloride (DBTCL) is a ubiquitous environmental contaminant. Prior research has established the reproductive toxicity, yet its precise impacts on embryonic developmental processes haven't been fully elucidated. The present study was designed to explore the influence of DBTCL exposure on early embryonic development in mice. This study demonstrated that exposure to DBTCL led to early embryonic developmental arrest. Through transcriptome sequencing, it was found that DBTCL exposure changed the overall gene expression profile in mouse 2-cell embryos. It suppressed the process of zygotic genome activation and the degradation of maternal mRNA, which consequently arrested the maternal-zygotic transition (MZT). Furthermore, mitochondrial function was also damaged under DBTCL treatment, as demonstrated by disordered mitochondrial distribution and a decline in mitochondrial membrane potential, and reduced ATP synthesis. Elevated levels of reactive oxygen species and superoxide anions in DBTCL-treated embryos suggested that DBTCL triggered oxidative stress. Moreover, embryos exposed to DBTCL exhibited significantly increased DNA damage. These changes were accompanied by reductions in the repressive histone marks H3K9me3, H3K27me2, and H3K27me3, which may be associated with the observed alterations in MZT. Collectively, these findings highlight the potential of DBTCL to inhibit early embryonic development, providing key experimental evidence for elucidating its developmental toxicity mechanisms.

Despite their well-established carcinogenicity, the effects of dietary polycyclic aromatic hydrocarbons (PAHs) on intestinal cells remain poorly understood. Additionally, toxicity studies are often based on animal models, and interspecies differences in xenobiotic metabolism may limit extrapolation to human exposure. The cytotoxic and toxicogenomic effects of seven food-relevant PAHs-benz[a]anthracene (BAA), benzo[a]pyrene (BaP), benzo[b]fluoranthene (BBF), benzo[k]fluoranthene (BKF), chrysene (CHRY), indeno[1,2,3-cd]pyrene (INDE), and dibenz[a,h]anthracene (DBAHA)-were investigated in mouse (C57BL/6), pig (IPEC-J2), and human (HIEC-6) intestinal epithelial cells. Viability assays showed that the LC₅₀ values of the PAHs for the mouse and pig models were 5-7 and 6-9 μg/mL, respectively, compared with 12-17 μg/mL in human cells. A conserved transcriptional response to PAH exposure was observed across all cell lines, including upregulation of xenobiotic metabolism genes (ahr, cyp1a1, cyp1b1, gst) and proliferation gene marker (ki67), and downregulation of barrier and junction genes (muc2, cdh1). PAH-treated HIEC-6 cells showed metabolic activation, with cyp1a1 and cyp1b1 upregulated more than 32-fold. Immunofluorescence microscopy experiments supported our findings of decreased MUC2 protein after PAH treatment. Because BaP may not fully account for the toxicity of all PAHs, our study provides relevant quantitative benchmarks for intestinal toxicity, advancing knowledge on current PAH exposure risk assessment.

Methylliberine (1,O2,7,9-tetramethyluric acid; 1,2,7,9-MU) and theacrine (1,3,7,9-tetramethyluric acid; 1,3,7,9-MU) are purine alkaloids found in a variety of botanicals and products marketed as dietary supplements. Despite their widespread use, extensive data on their human health effects are lacking. Therefore, methylliberine and theacrine were profiled using multiple new approach methods (NAMs): in silico metabolite predictions, in silico blood-brain barrier (BBB) permeability predictions, and in vitro assays for adenosine receptor binding (A1, A2A), functional activity (A2A), cytochrome P450 inhibition (CYP1A2), and phosphodiesterase inhibition (PDE3A, PDE4B, PDE4D). Like caffeine, methylliberine and theacrine were predicted to be metabolized via desmethylation by multiple in silico models. In silico predictions and cluster analysis also suggested that methylliberine and theacrine may permeate the BBB like caffeine. In vitro assays revealed that methylliberine and its metabolite 1,2,9-MU were CYP1A2 inhibitors (IC₅₀, 9.6 and 27 μM, respectively) that agreed with clinical observations and could lead to interactions with drugs and xenobiotics. Both methylliberine and theacrine were A2A receptor antagonists, suggesting a potential for stimulant effects, although their potencies (52-62% inhibition at 100 μM) were weaker than theophylline, paraxanthine, and caffeine (IC₅₀, 4.9-23.3 μM). Overall, this study highlights integration of multiple NAMs for profiling two purine alkaloids relevant to human health.

Combined exposure to environmental noise and carbon monoxide (CO) poses a growing threat to male reproductive health, yet the mechanisms underlying their combined toxicity remain incompletely understood. This study investigated the effects of combined noise and CO exposure on Sertoli cells and the blood-testis barrier (BTB), explored the potential epigenetic mechanisms involved, and evaluated the protective efficacy of pterostilbene (PTE) in male rats. Animals were exposed to noise (85 dB), CO (410 ppm), or both for 2 h/day over 60 days, with a subset receiving PTE (80 mg/kg/day). Combined exposure, but neither stressor alone, induced significant Sertoli cell loss, suppressed inhibin-B(INH-B) secretion, and disrupted BTB ultrastructure, accompanied by the coordinated downregulation of multiple junctional proteins including ZO-1, N-cadherin, and Claudin family members. Integrative transcriptomic and methylomic analyses suggested that this multi-target junctional impairment was associated with promoter hypermethylation-mediated transcriptional silencing, with Cldn5, Cldn9, Cldn18, and Cldn22 identified as representative targets. PTE co-treatment attenuated the aberrant methylation, restored junctional protein expression, and preserved BTB structural integrity. These findings suggest that promoter hypermethylation of BTB junctional genes may represent an important epigenetic mechanism underlying co-exposure-induced reproductive toxicity, and that PTE may serve as a promising protective intervention for populations at risk of combined environmental exposure.

Silicon dioxide nanoparticles (SiO₂NPs) are widely used as anti-caking agents (food additive E551). Their impact on the human gut microbiota is poorly understood. We evaluated the short-term effects of amorphous SiO₂NPs using a computer-controlled in vitro gastrointestinal digestion and batch culture fermentation model inoculated with fecal microbiota from a single healthy adult donor. Three doses were applied, low 3.15 mg, medium 63 mg and high 1,260 mg, corresponding to human-equivalent intakes of 0.09, 1.8 and 36 mg/kg body weight per day, spanning the reported mean dietary intake of E551 and an upper-bound exposure scenario; controls received deionized water. We monitored microbial community composition and metabolic activity by 16S rRNA sequencing, quantification of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), ammonium concentration, and antioxidant capacity (FRAP and DPPH) over 12 h. Over this window and at these doses, SiO₂NP treatment did not significantly alter α- or β-diversity, total SCFA or BCFA concentrations, ammonium, or FRAP/DPPH activity. However, taxonomic shifts were dose-dependent: low doses enriched Collinsella and depleted Flavonifractor, the medium dose enriched an Escherichia-Shigella amplicon sequence variant, and the high dose enriched Faecalibacterium and unclassified Clostridia while reducing Subdoligranulum, Faecalitalea and Flavonifractor (all false discovery rate < 0.05); an increase in Akkermansia at the high dose did not survive correction for multiple testing. Integrated multi-omics analysis (DIABLO) revealed that high-dose exposure weakened linkages between butyrate-producing Firmicutes and SCFAs and shifted the metabolic profile from butyrate toward propionate fermentation, accompanied by strengthened associations between proteolytic taxa, BCFAs and ammonium. These findings suggest that short-term exposure to SiO₂NPs induces subtle, concentration-dependent functional restructuring of the gut microbiota without overall diversity loss, although, as a single-donor in vitro study, the results are hypothesis-generating and require confirmation across multiple donors and longer exposures.

Cyanotoxin contamination of cyanobacteria- and microalgae-derived dietary supplements poses an emerging public health concern despite their widespread use for nutritional and therapeutic purposes. This review critically examines the occurrence of cyanotoxins in commercially available Arthrospira (formerly Spirulina), Aphanizomenon flos-aquae, and Chlorella supplements and comprehensively summarizes the molecular mechanisms underlying organ-specific toxicity induced by major cyanotoxins, including microcystins, nodularin, cylindrospermopsin, anatoxins, saxitoxins, and β-N-methylamino-L-alanine (BMAA). Tissue-specific accumulation and differential cellular susceptibility drive distinct toxicological outcomes. In the liver, cyanotoxins disrupt serine/threonine protein phosphatase signaling, mitochondrial function, and redox homeostasis, resulting in oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, and carcinogenesis. Neurotoxicity is characterized by excitotoxicity, impaired neurotransmission, calcium dysregulation, neuroinflammation, and neuronal death, whereas renal, gastrointestinal, cardiovascular, pulmonary, and reproductive toxicities involve interconnected mechanisms including oxidative damage, mitochondrial dysfunction, inflammatory signaling, and metabolic disruption. Despite substantial progress, important knowledge gaps remain regarding chronic low-dose exposure, bioavailability from dietary supplements, and long-term human health effects. Future studies integrating toxicokinetics, multi-omics approaches, and validated biomarkers are essential to strengthen risk assessment, improve regulatory oversight, and ensure the safety of cyanobacteria- and microalgae-derived dietary supplements.

p-Isopropylbenzyl alcohol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog benzyl alcohol (CAS # 100-51-6) show that p-isopropylbenzyl alcohol is not expected to be genotoxic and provide a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity, developmental toxicity, and local respiratory toxicity endpoints. The fertility endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to p-isopropylbenzyl alcohol is below the TTC (0.03 mg/kg/day). Data from read-across analog p-tolyl alcohol (CAS # 589-18-4) show that there are no safety concerns for p-isopropylbenzyl alcohol for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; p-isopropylbenzyl alcohol is not expected to be photoirritating/photoallergenic. The environmental endpoints were evaluated; p-isopropylbenzyl alcohol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients (RQs), based on its current volume of use (VoU) in Europe (EU), North America (NA), Asia-Pacific (AP), Japan (JP), and South America (SA) (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.