Microplastics (MPs) and benzo[a]pyrene (B[a]P) are prevalent environmental pollutants. Numerous studies have extensively reported their individual adverse effects on organisms. However, the combined effects and mechanisms of exposure in mammals remain unknown. Thus, this study aims to investigate the potential effects of oral administration of 0.5μm polystyrene (PS) MPs (1 mg/mL or 5 mg/mL), B[a]P (1 mg/mL or 5 mg/mL) and combined (1 mg/mL or 5 mg/mL) on 64 male SD rats by gavage method over 6-weeks. The results demonstrate that the liver histopathological examination showed that the liver lobules in the combined (5 mg/kg) group had blurred and loose boundaries, liver cord morphological disorders, and significant steatosis. The levels of AST, ALT, TC, and TG in the combined dose groups were significantly higher than those in the other groups, the combined (5 mg/kg) group had the lowest levels of antioxidant enzymes and the highest levels of oxidants. The expression of Nrf2 was lowest and the expression of P38, NF-κB, and TNF-α was highest in the combined (5 mg/kg) group. In conclusion, these findings indicate that the combination of PSMPs and B[a]P can cause the highest levels of oxidative stress and elicit markedly enhanced toxic effects, which cause severe liver damage.

Tire wear particles (TWPs) have caused increasing concerns due to their detrimental effects on the soil ecosystem. However, the role of weathering in altering the toxicity of TWP to soil organisms is poorly understood. In this study, the toxicity of original and photoaged TWP was compared using earthworms (Eisenia fetida) as soil model organisms. The obtained results indicated that photoaging of TWP resulted in an increase of environmentally persistent free radicals (EPFRs) from 3.69 × 1017 to 5.20 × 1017 spin/g. Meanwhile, photoaged TWP induced the changes of toxic endpoint in E. fetide, i.e., the increase of the weight loss and death ratio from 0.0425 to 0.0756 g/worm and 23.3 to 50% compared to original TWP under a 10% concentration, respectively. Analyses of transcriptomics, antioxidant enzyme activity, and histopathology demonstrated that the enhanced toxicity was mainly due to oxidative damage, which was induced by disruption in the antioxidant defense system. Free-radical quenching and correlation analysis further suggested that the excessive production of ex vivo reactive oxygen species, induced by EPFRs, led to the exhaustion of the antioxidant defense system. Overall, this work provides new insights into the potential hazard of the weathered TWP in a soil environment and has significant implications for the recycling and proper disposal of spent tire particles.

Since a mixed state of environmental contaminants, including microplastics (MPs), heavy metals, pharmaceuticals, and personal care products (PPCPs), exists in aquatic ecosystems, it is necessary to evaluate not only the adverse effects of exposure to a single stressor but to combined stressors. In this study, we exposed the freshwater water flea Daphnia magna to 2 μm MPs and triclosan (TCS), one of PPCPs, for 48 h to investigate the synergistic toxic consequences of simultaneous exposure to both pollutants. We measured in vivo endpoints, antioxidant responses, multixenobiotic resistance (MXR) activity, and autophagy-related protein expression via the PI3K/Akt/mTOR and MAPK signaling pathways. While MPs single exposure did not show toxic effects in water fleas, simultaneous exposure to TCS and MPs was associated with significantly greater deleterious effects in the form of increased mortality and alterations in antioxidant enzymatic activities compared with water fleas exposed to TCS alone. In addition, MXR inhibition was confirmed by measurement of the expression of P-glycoproteins and multidrug-resistance proteins in MPs-exposed groups, which led to the accumulation of TCS. Overall, these results suggest that simultaneous exposure to MPs and TCS resulted in higher TCS accumulation via MXR inhibition, leading to synergistic toxic effects such as autophagy in D. magna.

Two-dimensional molybdenum disulfide (2D MoS2) nanomaterials are seeing increased use in several areas, and this will lead to their inevitable release into soils. Surface defects can occur on MoS2 nanosheets during synthesis or during environmental aging processes. The mechanisms of MoS2 nanosheet toxicity to soil invertebrates and the role of surface defects in that toxicity have not been fully elucidated. We integrated traditional toxicity end points, targeted energy metabolomics, and transcriptomics to compare the mechanistic differences in the toxicity of defect-free and defect-rich MoS2 nanosheets (DF-MoS2 and DR-MoS2) to Eisenia fetida using a coelomocyte-based in vivo assessment model. After organism-level exposure to DF-MoS2 for 96 h at 10 and 100 mg Mo/L, cellular reactive oxygen species (ROS) levels were elevated by 25.6-96.6% and the activity of mitochondrial respiratory electron transport chain (Mito-RETC) complex III was inhibited by 9.7-19.4%. The tricarboxylic acid cycling and glycolysis were also disrupted. DF-MoS2 preferentially up-regulated subcellular component motility processes related to microtubules and caused mitochondrial fission. Unlike DF-MoS2, DR-MoS2 triggered an increased degree of mitochondrial fusion, as well as more severe oxidative stress. The activities of Mito-RETC complexes (I, III, IV, V) associated with oxidative phosphorylation were significantly inhibited by 22.8-68.6%. Meanwhile, apoptotic pathways were activated upon DR-MoS2 exposure, which together with the depolarization of mitochondrial membrane potential, mediated significant apoptosis. In turn, genes related to cellular homeostasis and energy release were up-regulated to compensate for DR-MoS2-induced energy deprivation. Our study indicates that MoS2 nanosheets have nanospecific effects on E. fetida and also that the role of surface defects from synthesis or that accumulate from environmental impacts needs to be fully considered when evaluating the toxicity of these 2D materials.

Iron particles present in drinking water distribution systems (DWDSs) could cause discoloration, while organic pollutants in DWDSs, such as perfluorooctanoic acid (PFOA), could be enriched by iron particles. However, little is known about the enhanced effects of PFOA and iron particles in DWDSs. To fill in these knowledge gaps, herein, iron-PFOA (FEP) particles were generated using residual chlorine as an oxidant in drinking water conditions and then separated into different sizes (ranging from small to large: FEP-S, FEP-M ，and FEP-L). FEP-S harbored the greatest cytotoxicity among the sizes. Interestingly, our data revealed that the PFOA released from FEP particles transformed into PFOS (perfluorooctane sulfonate) upon digestion in the gastrointestinal environment (GI), and FEP-L bored the strongest transformation, showing a toxicity profile that was distinct from that of FEP-S. Furthermore, mechanistic studies revealed that FEP per se should be accountable for the conversion of PFOA to PFOS dependent on the generation of hydroxyl radicals (·OH) in GI, and that FEP-L revealed the greatest production of ·OH. Collectively, these results showed how iron particles and PFOA could result in enhanced toxicity effects in drinking water: (i) PFOA could increase the toxicity of iron particles by reducing particle size and inducing higher generation of ·OH; (ii) iron particles could induce the transformation of PFOA into more toxic PFOS through digestion.

Early life exposure to environmental chemicals can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concentrations for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chemical, was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, respectively. The effects on cell viability and neurite length were measured based on image analysis in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often observed for hydrophilic chemicals, which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chemicals showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concentrations for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the observed effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.

Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether \"microarray profiles\" could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. We compared the mRNA responses within bone marrow of Sprague-Dawley rats after a single 30 min treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control for 1, 6, and 24 h. We also examined the histopathology of the bone marrow following all treatments. Drug-related histopathological lesions were limited to bone marrow hypocellularity for animals dosed with either agent alone or in combination. Lesions had an earlier onset and higher incidence for animals given topotecan alone or in combination with oxaliplatin. Severity increased from mild to moderate when topotecan was administered prior to oxaliplatin compared with administering oxaliplatin first. Notably, six patterns of co-expressed genes were detected at the 1 h time point that indicate regulatory expression of genes that are dependent on the order of the administration. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. These data also demonstrate the potential for early mRNA patterns derived from target organs of toxicity to inform toxicological risk and molecular mechanisms for agents given in combination.