The key characteristics of cardiotoxicity for the pervasive pollutant phenanthrene.

The key characteristic (KCs) framework has been used previously to assess the carcinogenicity and cardiotoxicity of various chemical and pharmacological agents. Here, the 12 KCs of cardiotoxicity are used to evaluate the previously reported cardiotoxicity of phenanthrene (Phe), a tricyclic polycyclic aromatic hydrocarbon (PAH), and major component of fossil fuel-derived air pollution. Phe is a semi-volatile pollutant existing in both the gas phase and particle phase through adsorption onto or into particulate matter (PM). Phe can translocate across the airways and gastrointestinal tract into the systemic circulation, enabling body-wide effects. Our evaluation based on a comprehensive literature review, indicates Phe exhibits 11 of the 12 KCs for cardiotoxicity. These include adverse effects on cardiac electromechanical performance, the vasculature and endothelium, immunomodulation and oxidative stress, and neuronal and endocrine control. Environmental agents that have similarly damaging effects on the cardiovascular system are heavily regulated and monitored, yet globally there is no air quality regulation specific for PAHs like Phe. Environmental monitoring of Phe is not the international standard with benzo[a]pyrene being frequently used as a proxy despite the two PAH species exhibiting significant differences in sources, concentration variations and toxic effects. The evidence summarised in this evaluation highlights the need to move away from proxied PAH measurements and develop a monitoring network capable of measuring Phe concentration. It also stresses the need to raise awareness amongst the medical community of the potential cardiovascular impact of PAH exposure. This will allow the production of mitigation strategies and possibly the development of new policies for the protection of the societal groups most vulnerable to cardiovascular disease.

PAH bioremediation with Rhodococcus rhodochrous ATCC 21198: Impact of cell immobilization and surfactant use on PAH treatment and post-remediation toxicity.

Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental contaminants that are harmful to ecological and human health. Bioremediation is a promising technique for remediating PAHs in the environment, however bioremediation often results in the accumulation of toxic PAH metabolites. The objectives of this research were to demonstrate the cometabolic treatment of a mixture of PAHs by a pure bacterial culture, Rhodococcus rhodochrous ATCC 21198, and investigate PAH metabolites and toxicity. Additionally, the surfactant Tween ® 80 and cell immobilization techniques were used to enhance bioremediation. Total PAH removal ranged from 70-95% for fluorene, 44-89% for phenanthrene, 86-97% for anthracene, and 6.5-78% for pyrene. Maximum removal was achieved with immobilized cells in the presence of Tween ® 80. Investigation of PAH metabolites produced by 21198 revealed a complex mixture of hydroxylated compounds, quinones, and ring-fission products. Toxicity appeared to increase after bioremediation, manifesting as mortality and developmental effects in embryonic zebrafish. 21198's ability to rapidly transform PAHs of a variety of molecular structures and sizes suggests that 21198 can be a valuable microorganism for catalyzing PAH remediation. However, implementing further treatment processes to address toxic PAH metabolites should be pursued to help lower post-remediation toxicity in future studies.

Remediation of phenanthrene by highly efficient CdS-SnS photocatalyst and its cytotoxic assessments.

Cadmium sulfide-tin sulfide (CdS-SnS) nanoparticles are a novel kind of photocatalyst. These CdS-SnS nanoparticles are synthesized and characterized using UV-Vis, FT-IR, XRD, SEM-EDX, and DLS techniques, to understand their size distribution, crystalline nature, morphology, shape, optical properties, and elemental composition. This research offers insight into the efficient photocatalytic degradation of Phenanthrene (PHE) using CdS-SnS. The CdS-SnS NPs as photocatalyst can effectively photodegrade the polycyclic aromatic hydrocarbons (PAH) such as phenanthrene under simulated solar and UV light. UV-vis spectra of these nanoparticles exhibit peaks at 365 and 546 cm-1 respectively, the mean size of the CdS-SnS NPs in DLS is determined to be 78 nm. The CdS-SnS stretching frequency was observed at wave numbers below 700 cm-1, the absorption peak at 1123 cm-1 indicates the presence of C-N stretch or CS bond of thiourea, while the peak at 1350.38 cm-1 corresponds to the tris-amine C-N stretch in FT-IR. Additionally, the peaks observed at 2026 cm-1 indicate the presence of isothiocyanate (NCS). 1456.23 cm-1 represents the asymmetric scissor deformation vibration. EDAX revealed the presence of elemental Cd and Sn oxides. The antimicrobial studies showed that the CdS-SnS NPs at the concentration of 150 µg/mL, exhibit maximum inhibition (15 ± 1.25 mm) against the strains Proteus mirabilis followed by Staphylococcus epidermidis and Clostridium spp. Among fungal strains Colletotrichum spp. exhibits the maximum zone of inhibition (9 ± 0.25). This research also observed the cytotoxic effects of CdS-SnS NPs on HepG2 and ZF4 cells. HepG2 cells exhibited 50% inhibition at 50 µg/mL and 70% inhibition at 100 µg/mL concentrations, while ZF4 cells exhibited 50% inhibition at 50 µg/mL and 78% inhibition at 100 µg/mL concentrations, respectively. The parameters like concentration of PHE, concentration of CdS-SnS NPs, pH, and sources of irradiation on batch adsorption were examined to maximize the efficiency of the photodegradation process.

Chronic exposure to low levels of phenanthrene induces histological damage and carcinogenic risk in the uterus of female mice.

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon with low molecular weight, is detected in the environment at high frequency. To study the toxic effects of Phe on the uterine structure and function, female Kunming mice were exposed to Phe (0.05, 0.5, 5 ng/mL) for 270 days by drinking water. Pathological alterations and their action pathways were analyzed using immunohistochemical and biomolecular technology. Phe significantly increased the percentage of blood vessel area, the number of endometrial neutrophils (indicating the occurrence of inflammation), collagen deposition (indicating fibrosis), and the percentage of Ki-67-positive cells (indicating carcinogenesis) in the uterus. Transcriptome sequencing identified differentially expressed genes that were mainly enriched in some signaling pathways, including inflammation and carcinogenesis, suggesting a carcinogenic risk in the Phe-exposed uterus. Elevated serum estrogen levels and decreased progesterone levels exhibited a disturbance of steroid hormone balance, which might be related to uterine damage. Upregulated protein levels of uterine androgen receptor and estrogen receptor α were linked to the pathological effects. Most of the effects exhibited a nonmonotonic dose response, which might be attributed to the corresponding change in the serum levels of Phe. The results suggest that exposure to low levels of Phe could exert adverse effects on the uterus.

Structure-activity relationships for alkyl-phenanthrenes support two independent but interacting synergistic models for PAC mixture potency.

Multiple lines of evidence at whole animal, cellular and molecular levels implicate polycyclic aromatic compounds (PACs) with three rings as drivers of crude oil toxicity to developing fish. Phenanthrene (P0) and its alkylated homologs (C1- through C4-phenanthrenes) comprise the most prominent subfraction of tricyclic PACs in crude oils. Among this family, P0 has been studied intensively, with more limited detail available for the C4-phenanthrene 1-methyl-7-isopropyl-phenanthrene (1-M,7-IP, or retene). While both compounds are cardiotoxic, P0 impacts embryonic cardiac function and development through direct blockade of K+ and Ca2+ currents that regulate cardiomyocyte contractions. In contrast, 1-M,7-IP dysregulates aryl hydrocarbon receptor (AHR) activation in developing ventricular cardiomyocytes. Although no other compounds have been assessed in detail across the larger family of alkylated phenanthrenes, increasing alkylation might be expected to shift phenanthrene family member activity from K+/Ca2+ ion current blockade to AHR activation. Using embryos of two distantly related fish species, zebrafish and Atlantic haddock, we tested 14 alkyl-phenanthrenes in both acute and latent developmental cardiotoxicity assays. All compounds were cardiotoxic, and effects were resolved into impacts on multiple, highly specific aspects of heart development or function. Craniofacial defects were clearly linked to developmental cardiotoxicity. Based on these findings, we suggest a novel framework to delineate the developmental toxicity of petrogenic PAC mixtures in fish, which incorporates multi-mechanistic pathways that produce interactive synergism at the organ level. In addition, relationships among measured embryo tissue concentrations, cytochrome P4501A mRNA induction, and cardiotoxic responses suggest a two-compartment toxicokinetic model that independently predicts high potency of PAC mixtures through classical metabolic synergism. These two modes of synergism, specific to the sub-fraction of phenanthrenes, are sufficient to explain the high embryotoxic potency of crude oils, independent of as-yet unmeasured compounds in these complex environmental mixtures.

Group 1 innate lymphoid cell activation via recognition of NKG2D and liver resident macrophage MULT-1: Collaborated roles in triptolide induced hepatic immunotoxicity in mice.

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.

Low soil Moisture Slows Uptake and Elimination Rates of Phenanthrene in Springtails.

This study investigated the influence of soil water status on the toxicokinetics of phenanthrene in the springtail Folsomia candida allowing estimation of uptake and elimination rates at two contrasting soil water potentials. Fitting a three-phase model to the observations showed that uptake rate (ku) was almost two times higher in moist soil (-2 kPa) than in dry soil (-360 kPa). During the first days of the exposure, elimination rate (ke) was not significantly different in moist and dry soil, but after eight days ke had increased significantly more in moist soil than in dry soil. Our results confirm the general notion that the exposure route via soil pore water is important. Understanding the significance of soil moisture in exposure and effects of contaminants on soil invertebrates is crucial for assessing the ecological risks associated with soil pollution in a changing climate.

Selective Antitumor Effect and Lower Toxicity of Mitochondrion-Targeting Derivatization of Triptolide.

Triptolide has a significant antitumor activity, but its toxicity limits its clinical application. As the mitochondrion-targeting strategy showed an advantage in selective antitumor effect based on the higher mitochondrial membrane potential (MMP) in tumor cells than normal cells, the lipophilic cations triphenylphosphonium and E-4-(1H-indol-3-yl vinyl)-N-methylpyridinium iodide (F16) were selected as targeting carriers for structural modification of triptolide. The derivatives bearing F16 generally retained most antitumor activities, overcame its inhibition plateau phenomena, and enhanced its selective antitumor effect in lung cancer. The representative derivative F9 could accumulate in the mitochondria of NCI-H1975 cells, inducing apoptosis and a dose-dependent increase in intracellular reactive oxygen species and reducing MMP. Moreover, no effects were observed in normal cells BEAS-2B. In vivo studies showed that the developmental, renal, and liver toxicities of F9 to zebrafish were significantly lower than those of triptolide. This study provides a promising idea to relieve the toxicity problem of triptolide.

The implementation of ZnS-SnS BM NPs for phenanthrene degradation: An adsorptive photocatalyst approach and its toxicity studies in adult zebrafish.

Phenanthrene is a persistent organic pollutant released by numerous industries. The purpose of the study is to construct a batch reactor for phenanthrene degradation using a bimetallic (BM) ZnS-SnS nanoparticle as a photocatalyst. ZnS-SnS BM NPs were used as a photocatalyst, employed from precursors Zinc acetate dihydrate and tin (II) chloride dihydrate, with crystalline cubic-shaped particle sizes. ZnS-SnS BM NPs were utilized in batch adsorption assays to assess the impact of phenanthrene degradation parameters on various PAHs (Polycyclic aromatic hydrocarbons) concentrations, pH levels, and irradiation sources. Adsorption kinetic and isotherm tests revealed that the pseudo-first order kinetic model, pseudo-second order kinetic model, and Langmuir isotherm model all fit effectively with the effective phenanthrene degradation using ZnS-SnS BM NPs. The degraded product were analyzed for GC-MS, revealing that organic pollutant phenanthrene was converted into harmless by-products like n-hexadecenoic acid, oleic acid, and octadecanoic acid. The toxicity of phenanthrene was observed to decrease with an increase in ZnS-SnS BM NPs concentration. ZnS-SnS BM NP concentration of 150 µg/mL, the zone of inhibition values was recorded highest zone of inhibition (19 ± 1.2 mm) against the strains S. epidermis followed by B. cereus and Clostridium spp. Further adult zebrafish were found to be less toxic to ZnS-SnS BM NPs after 96 h of exposure, with an LD50 of 100 µg/L. The toxicity escalated as concentrations increased. Behavior test showed normal swimming, learning, and memory in open tank and T-maze tests, while 100 µg/L showed pausing/frozen time in zebra fish therefore low doses are considered safe. Hence by employing ZnS-SnS BM NPs can be engaged in waste water treatment for PAH degradation.

Dual effect of polyaromatic hydrocarbons on sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity of a teleost fish (Oncorhynchus mykiss).

Polycyclic aromatic hydrocarbons (PAHs) are embryo- and cardiotoxic to fish that might be associated with improper intracellular Ca2+ management. Since sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a major regulator of intracellular Ca2+, the SERCA activity and the contractile properties of rainbow trout (Oncorhynchus mykiss) ventricle were measured in the presence of 3- and 4-cyclic PAHs. In unfractionated ventricular homogenates, acute exposure of SERCA to 0.1-1.0 µM phenanthrene (Phe), retene (Ret), fluoranthene (Flu), or pyrene (Pyr) resulted in concentration-dependent increase in SERCA activity, except for the Flu exposure, with maximal effects of 49.7-83 % at 1 µM. However, PAH mixture did not affect the contractile parameters of trout ventricular strips. Similarly, all PAHs, except Ret, increased the myotomal SERCA activity, but with lower effect (27.8-40.8 % at 1 µM). To investigate the putative chronic effects of PAHs on SERCA, the atp2a2a gene encoding trout cardiac SERCA was expressed in human embryonic kidney (HEK) cells. Culture of HEK cells in the presence of 0.3-1.0 µM Phe, Ret, Flu, and Pyr for 4 days suppressed SERCA expression in a concentration-dependent manner, with maximal inhibition of 49 %, 65 %, 39 % (P < 0.05), and 18 % (P > 0.05), respectively at 1 µM. Current findings indicate divergent effects of submicromolar PAH concentrations on SERCA: stimulation of SERCA activity in acute exposure and inhibition of SERCA expression in chronic exposure. The depressed expression of SERCA is likely to contribute to the embryo- and cardiotoxicity of PAHs by depressing muscle function and altering gene expression.

The combined effects of phenanthrene and micro-/nanoplastics mixtures on the cellular stress responses of the thick-shell mussel Mytilus coruscus.

Pollution with complex mixtures of contaminants including micro- and nano-plastics (MNPs) and organic pollutants like polycyclic aromatic hydrocarbons (PAH) poses a major threat to coastal marine ecosystems. Toxic mechanisms of contaminant mixtures are not well understood in marine organisms. We studied the effects of single and combined exposures to polycyclic aromatic hydrocarbon phenanthrene (Phe) and MNPs mixture with sizes of 70 nm, 5 µm and 100 µm on the immune health and oxidative stress parameters in the thick-shell mussel Mytilus coruscus. Immune cells (hemocytes) were more sensitive to the pollutant-induced oxidative stress than the gills. In hemocytes of co-exposed mussels, elevated mortality, lower lysosomal content, high production of reactive oxygen species (ROS) and decrease mitochondrial were found. Disparate responses of antioxidant enzymes in the hemolymph (e.g. increased superoxide dismutase (SOD) activity without a corresponding increase in catalase (CAT) in Phe exposures and an increase in CAT without a change in SOD in MNPs exposures) suggests misbalance of the antioxidant defense in the pollutant-exposed mussels. Gill lacked pronounced oxidative stress response showing a decline in ROS and antioxidant levels. Tissue-specific single and combined effects of Phe and MNPs suggest variation in bioavailability and/or different sensitivity to these pollutants in the studied tissues. Notably, the combined effects of MNPs and Phe were additive or antagonistic, showing that MNPs do not enhance and occasionally mitigate the toxic effects of Phe on the hemocytes and the gills of the mussels. Overall, our study sheds light on the impact of long-term exposure to MNPs and Phe mixtures on mussels, showing high sensitivity of the immune system and modulation of the Phe toxicity by MNPs co-exposure. These findings that may have implications for understanding the impacts of combined PAH and MNPs pollution on the health of mussel populations from polluted coastal habitats.

Global Air Pollutant Phenanthrene and Arrhythmic Outcomes in a Mouse Model.

BACKGROUND: The three-ringed polycyclic aromatic hydrocarbon (PAH) phenanthrene (Phe) has been implicated in the cardiotoxicity of petroleum-based pollution in aquatic systems, where it disrupts the contractile and electrical function of the fish heart. Phe is also found adsorbed to particulate matter and in the gas phase of air pollution, but to date, no studies have investigated the impact of Phe on mammalian cardiac function. OBJECTIVES: Our objectives were to determine the arrhythmogenic potential of acute Phe exposure on mammalian cardiac function and define the underlying mechanisms to provide insight into the toxicity risk to humans. METHODS: Ex vivo Langendorff-perfused mouse hearts were used to test the arrhythmogenic potential of Phe on myocardial function, and voltage- and current-clamp recordings were used to define underlying cellular mechanisms in isolated cardiomyocytes. RESULTS: Mouse hearts exposed to ∼8µM Phe for 15-min exhibited a significantly slower heart rate (p=0.0006, N=10 hearts), a prolonged PR interval (p=0.036, N=8 hearts), and a slower conduction velocity (p=0.0143, N=7 hearts). Whole-cell recordings from isolated cardiomyocytes revealed action potential (AP) duration prolongation (at 80% repolarization; p=0.0408, n=9 cells) and inhibition of key murine repolarizing currents-transient outward potassium current (Ito) and ultrarapid potassium current (IKur)-following Phe exposure. A significant reduction in AP upstroke velocity (p=0.0445, n=9 cells) and inhibition of the fast sodium current (INa; p=0.001, n=8 cells) and calcium current (ICa; p=0.0001) were also observed, explaining the slowed conduction velocity in intact hearts. Finally, acute exposure to ∼8µM Phe significantly increased susceptibility to arrhythmias (p=0.0455, N=9 hearts). DISCUSSION: To the best of our knowledge, this is the first evidence of direct inhibitory effects of Phe on mammalian cardiac electrical activity at both the whole-heart and cell levels. This electrical dysfunction manifested as an increase in arrhythmia susceptibility due to impairment of both conduction and repolarization. Similar effects in humans could have serious health consequences, warranting greater regulatory attention and toxicological investigation into this ubiquitous PAH pollutant generated from fossil-fuel combustion. https://doi.org/10.1289/EHP12775.

Endophytic Bacillus sp. R1 and Its Roles in Assisting Phytoremediation and Alleviating the Toxicity of Aluminum Combined Phenanthrene Contaminations in Brassica napus.

The release of organic and inorganic contaminants into soil from industry, agriculture, and urbanization has become a major issue of international concern, particularly the heavy metals such as aluminum (Al) and the chemical phenanthrene (PHE). Due to their potential toxicity and non-biodegrade in the environment, efficient remediation methods are urgently needed. Recently, research has comprehensively discussed using plants and their endophytes in bioremediation efforts. Endophytic Bacillus sp. R1, isolated from Brassica napus permanently contaminated with Al and PHE, has growth-promoting properties and can efficiently detoxify these contaminants. The pot experiment indicated that compared to the Al combined PHE contaminated soil alone treatment, the R1 treatment led to increased Al accumulation in canola roots across different levels of PHE, Al, and combined PHE and Al contamination. However, Al accumulation in canola shoots and seeds remained unchanged for all treatments. Moreover, PHE in canola roots and shoots was decreased by R1 inoculation and thereby reducing 26.12-60.61% PHE translocated into canola seeds. Additionally, R1 inoculation significantly increased the proportion of extractable Al and, decreased the proportion of acid-soluble inorganic Al and humic-acid Al, but did not affect the concentration of organically complexed Al. In summary, endophyte R1 can degrade PHE, improve canola roots' Al uptake by increasing soil available Al, and scavenge the reactive oxygen species through production of antioxidant enzymes to help alleviate the toxicity of canola co-contaminated with aluminum and phenanthrene.

Integument colour change: Tracking delayed growth of Oppia nitens as a sub-lethal indicator of soil toxicity.

Growth is an important toxicity end-point in ecotoxicology but is rarely used in soil ecotoxicological studies. Here, we assessed the growth change of Oppia nitens when exposed to reference and heavy metal toxicants. To assess mite growth, we developed an image analysis methodology to measure colour spectrum changes of the mite integument at the final developmental stage, as a proxy for growth change. We linked the values of red, green, blue, key-black, and light colour of mites to different growth stages. Based on this concept, we assessed the growth change of mites exposed to cadmium, copper, zinc, lead, boric acid, or phenanthrene at sublethal concentrations in LUFA 2.2 soil for 14 days. Sublethal effects were detected after 7 days of exposure. The growth of O. nitens was more sensitive than survival and reproduction when exposed to copper (EC50growth = 1360 mg/kg compared to EC50reproduction = 2896 mg/kg). Mite growth sensitivity was within the same order of magnitude to mite reproduction when exposed to zinc (EC50growth = 1785; EC50reproduction = 1562 mg/kg). At least 25% of sublethal effects of boric acid and phenanthrene were detected in the mites but growth was not impacted when O. nitens were exposed to lead. Consistent with previous studies, cadmium was the most toxic metal to O. nitens. The mite growth pattern was comparable to mite survival and reproduction from previous studies. Mite growth is a sensitive toxicity endpoint, ecologically relevant, fast, easy to detect, and can be assessed in a non-invasive fashion, thereby complimenting existing O. nitens testing protocols.

Microplastics reduced bioavailability and altered toxicity of phenanthrene to maize (Zea mays L.) through modulating rhizosphere microbial community and maize growth.

Due to its large specific surface area and great hydrophobicity, microplastics can adsorb polycyclic aromatic hydrocarbons (PAHs), affecting the bioavailability and the toxicity of PAHs to plants. This study aimed to evaluate the effects of D550 and D250 (with diameters of 550 µm and 250 µm) microplastics on phenanthrene (PHE) removal from soil and PHE accumulation in maize (Zea mays L.). Moreover, the effects of microplastics on rhizosphere microbial community of maize grown in PHE-contaminated soil would also be determined. The results showed that D550 and D250 microplastics decreased the removal of PHE from soil by 6.5% and 2.7% and significantly reduced the accumulation of PHE in maize leaves by 64.9% and 88.5%. Interestingly, D550 microplastics promoted the growth of maize and enhanced the activities of soil protease and alkaline phosphatase, while D250 microplastics significantly inhibited the growth of maize and decreased the activities of soil invertase, alkaline phosphatase and catalase, in comparison with PHE treatment. In addition, microplastics changed the rhizosphere soil microbial community and reduced the relative abundance of PAHs degrading bacteria (Pseudomonas, Massilia, Proteobacteria), which might further inhibit the removal of PHE from soil. This study provided a new perspective for evaluating the role of microplastics on the bioavailability of PHE to plants and revealing the combined toxicity of microplastics and PHE to soil microcosm and plant growth.

Decoding the biological toxicity of phenanthrene on intestinal cells of Eisenia fetida: Effects, toxicity pathways and corresponding mechanisms.

Phenanthrene is frequently detected and exists extensively in the soil environment, and its residues inevitably impose a significant threat to soil organisms. Exposure to and toxicity of phenanthrene on earthworms has been extensively studied before, however, the possible mechanisms and related pathways associated with phenanthrene-triggered toxicity at the intestinal cell level remain unclear. Herein, primary intestinal cells isolated from Eisenia fetida (Annelida, Oligochaeta) intestine were used as targeted receptors to probe the molecular mechanisms involved in ROS-mediated damaging effects and the potential pathways of phenanthrene-induced toxicity at cellular and sub-cellular levels. Results indicated that phenanthrene exposure induced oxidative stress by activating intracellular ROS (elevated O2-, H2O2, and OH- content) bursts in E. fetida intestinal cells, causing various oxidative damage effects, including lipid peroxidation (increased MDA content), protein oxidation (enhanced PCO levels), and DNA damage (enhanced 8-OHdG levels). The enzymatic and non-enzymatic strategies in earthworm cells were activated to mitigate these detrimental effects by regulating ROS-mediated pathways involving defense regulation. Also, phenanthrene stress destroyed the cell membrane of E. fetida intestinal cells, resulting in cellular calcium homeostasis disruption and cellular energetic alteration, ultimately causing cytotoxicity and cell apoptosis/death. More importantly, the mitochondrial dysfunction in E. fetida cells was induced by phenanthrene-caused mitochondrial membrane depolarization, which in turn caused un-controlled ROS burst and induced apoptosis through mitochondria-mediated caspase-3 activation and ROS-mediated mitochondrial-dependent pathway. Furthermore, exposure to phenanthrene activated an abnormal mRNA expression profile associated with defense regulation (e.g., Hsp70, MT, CRT, SOD, CAT, and GST genes) in E. fetida intestinal cells, resulting in various cellular dysfunctions and pathological conditions, eventually, apoptotic cell death. Taken together, this study offers valuable insights for probing the toxic effects and underlying mechanisms posed by phenanthrene at the intestinal cell level, and is of great significance to estimate the detrimental side effects of phenanthrene on soil ecological health.

Triptolide induces PANoptosis in macrophages and causes organ injury in mice.

Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.

Interactions between phenanthrene and polystyrene micro/nano plastics: Implications for rice (Oryza sativa L.) toxicity.

Micro/nano plastics (MPs/NPs) are widely distributed and are one of the global pollutants of current concern. Micro/nano plastics can adsorb a variety of persistent organic pollutants, and different particle sizes and surface charges affect the biological effects of MPs/NPs. Therefore, how the compound pollution of MPs/NPs with different particle sizes and organic pollutants produces toxic effects on plants needs to be further studied. We investigated the toxic effects of phenanthrene (Phe) and amino-modified PS (PS-NH2) with two particle sizes (50 nm, 5 µm) on rice. The stress mechanism of PS-NH2 was different between the two particle sizes. Moreover, 50 nm PS-NH2 inhibited stomatal conductance and transpiration rate, reduced photosynthetic rate, significantly enriched GO functions such as "DNA repair" and "DNA double-strand break," and caused severe DNA damage in rice. Notably, 5 µm PS-NH2 affected the gene expression of "photosynthetic lighting" and "photosynthetic antenna protein" in rice, decreased chlorophyll content, and inhibited rice growth. The toxicity of 50 nm PS-NH2 was stronger. In addition, we found that Phe reduced the toxicity of PS-NH2 with different particle sizes, and the relief effect of 50 nm PS-NH2+Phe was more evident. Further, 50 nm PS-NH2+Phe alleviated the toxicity by stimulating the activities of antioxidant enzymes, reducing oxidative damage to chloroplasts, and inhibiting photosynthesis. However, 5 µm PS-NH2+Phe can reduce the stress by reducing the degree of membrane lipid peroxidation, activating metabolic pathways related to the cell wall and cell membrane formation, and plant antitoxin biosynthesis. The results contribute to the understanding of the mechanism of toxicity of MPs/NPs and polycyclic aromatic hydrocarbons (PAHs) to crops.

Synergistic, antagonistic, and additive effects of naphthalene, phenanthrene, fluoranthene and benzo(k)fluoranthene on Artemia franciscana nauplii and adult.

Polycyclic aromatic hydrocarbons (PAHs) are widespread across the globe and can be highly toxic for the marine environment. This research investigated the short-term (48 h of exposure) effects of PAHs mixtures on the nauplii and adult of crustacean Artemia franciscana considering the impact in term of toxicity and changes in gene expression. Results showed that all combinations caused additive or synergic effects with the exception of naphthalene + phenanthrene (NAP + PHE; Combination Index (CI) = 22.3), while naphthalene + benzo(k)fluoranthene (NAP + BkF; CI = 7.8) mixture evidenced an antagonistic effect. Real-time qPCR showed that all mixtures impacted the expression level of the five known genes involved in Artemia stress response. The effects of PAHs at environmental concentrations on both adult and nauplii suggested the need for further investigations about the impact of such contaminants on the marine biota considering that crustaceans can accumulate PAHs at concentrations comparable to those assessed in the present study.

Recent advances in the pharmacological applications and liver toxicity of triptolide.

Triptolide is a predominant active component of Triptergium wilfordii Hook. F, which has been used for the treatment of cancers and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and diabetic nephropathy. Therefore, triptolide and its derivates are considered to have promising prospects for development into drugs. However, the clinical application of triptolide is limited due to various organ toxicities, especially liver toxicity. The potential mechanism of triptolide-induced hepatotoxicity has attracted increasing attention. Over the past five years, studies have revealed that triptolide-induced liver toxicity is involved in metabolic imbalance, oxidative stress, inflammations, autophagy, apoptosis, and the regulation of cytochrome P450 (CYP450) enzymes, gut microbiota and immune cells. In this review, we summarize the pharmacological applications and hepatotoxicity mechanism of triptolide, which will provide solid theoretical evidence for further research of triptolide.