Phe Exposure Research Articles

Single and combined effects of phenanthrene and cadmium on oxidative stress and detoxification related biomarkers in clams (Meretrix meretrix)

Biomarkers concerning antioxidant reactions and detoxification metabolics were evaluated in Meretrix meretrix exposed to cadmium (Cd, 10 μg/L) and phenanthrene (PHE, 100 μg/L) individually and in combination (10 μg/L Cd + 100 μg/L PHE) for 7 days. The accumulation of Cd and PHE measured in the digestive gland, gill, mantle, and axe foot of the clam showed significant increase in combination treatment and it was higher than the single Cd or single PHE treatment. The activities of oxidative stress-related enzymes, the expression of Cu/Zn SOD, and the content of MDA increased after Cd and PHE exposure in the digestive gland and gill at most cases. In the digestive gland, CAT gene expression was significantly induced in Cd-single group and significantly inhibited in PHE-single group and Cd-PHE mixed group at both day 3 and day 7; in the gill, CAT gene expression was significantly inhibited in all groups at day 3 and except for Cd-single group at day 7. MT expression was significantly induced in Cd-single and Cd-PHE mixed groups at day 7, while hsp70 expression was significantly inhibited in PHE-single and Cd-PHE mixed groups at day 7. The results indicated that SOD, CAT, GST, MDA, Cu/Zn SOD, CAT, MT and hsp70 were sensitive to cadmium and PHE in a water environment, and can be used as indicators of marine heavy metal pollution.

Transcriptome Profiling of Phenylalanine-Treated Human Neuronal Model: Spotlight on Neurite Impairment and Synaptic Connectivity.

Phenylketonuria (PKU) is the most common inherited disorder of amino acid metabolism, characterized by high levels of phenylalanine (Phe) in the blood and brain, leading to cognitive impairment without treatment. Nevertheless, Phe-mediated brain dysfunction is not fully understood. The objective of this study was to address gene expression alterations due to excessive Phe exposure in the human neuronal model and provide molecular advances in PKU pathophysiology. Hence, we performed NT2/D1 differentiation in culture, and, for the first time, we used Phe-treated NT2-derived neurons (NT2/N) as a novel model for Phe-mediated neuronal impairment. NT2/N were treated with 1.25 mM, 2.5 mM, 5 mM, 10 mM, and 30 mM Phe and subjected to whole-mRNA short-read sequencing. Differentially expressed genes (DEGs) were analyzed and enrichment analysis was performed. Under three different Phe concentrations (2.5 mM, 5 mM, and 10 mM), DEGs pointed to the PREX1, LRP4, CDC42BPG, GPR50, PRMT8, RASGRF2, and CDH6 genes, placing them in the context of PKU for the first time. Enriched processes included dendrite and axon impairment, synaptic transmission, and membrane assembly. In contrast to these groups, the 30 mM Phe treatment group clearly represented the neurotoxicity of Phe, exhibiting enrichment in apoptotic pathways. In conclusion, we established NT2/N as a novel model for Phe-mediated neuronal dysfunction and outlined the Phe-induced gene expression changes resulting in neurite impairment and altered synaptic connectivity.

Metabolic profile changes of zebrafish larvae in the single- and co-exposures of microplastics and phenanthrene

Microplastics (MPs) are ubiquitous in the environment, and can adsorb organic contaminants (OCs) and be taken by various microorganisms and organisms, which could eventually lead to risk to humans. In this study, the phenotypic changes and metabolic profile alternations of zebrafish in the single- and co-exposure of MPs and phenanthrene (Phe) were investigated. The results showed that significantly higher tail malformation rate and edema rate in zebrafish induced by MPs can be enhanced due to the co-existence of Phe. The metabolomic analysis revealed that both synergistic and antagonistic effects of MPs and Phe on the metabolic alternation of zebrafish larvae exist, since unique perturbations of metabolites or pathways were found in all of the three exposure scenarios. Based on Partial least squares-discriminant analysis, porphine, ribose, and L-glutamic acid were the most important metabolites resulting in the difference between the treated and control groups in the MP exposure, Phe exposure and co-exposure, respectively. Two dysregulated pathways namely d-glutamine and D-glutamate metabolism, and alanine, aspartate and glutamate metabolism were significantly affected in the co-exposure while not in either of the single exposure. These findings provide new insights into the toxic effects of MPs on aquatic organisms, and further studies on combined effects of MPs and OCs are suggested to be conducted.

Phenanthrene-induced hyperuricemia with intestinal barrier damage and the protective role of theabrownin: Modulation by gut microbiota-mediated bile acid metabolism

Hyperuricemia is prevalent globally and potentially linked to environmental pollution. As a typical persistent organic pollutant, phenanthrene (Phe) poses threats to human health through biomagnification. Although studies have reported Phe-induced toxicities to multiple organs, its impact on uric acid (UA) metabolism remains unclear. In this study, data mining on NHANES 2001–2016 indicated a positive correlation between Phe exposure and the occurrence of hyperuricemia in population. Subsequently, adolescent Balb/c male mice were orally exposed to Phe at a dosage of 10 mg/kg bw every second day for 7 weeks, resulting in dysfunction of intestinal UA excretion and disruption of the intestinal barrier. Utilizing intestinal organoids, 16S rRNA sequencing of gut microbiota, and targeted metabolomic analysis, we further revealed that an imbalance in bile acid metabolism derived from gut microbiota might mediate the intestinal barrier damage. Additionally, the tea extract theabrownin (TB) effectively improved Phe-induced hyperuricemia and intestinal dysfunction at a dose of 320 mg/kg bw per day. In conclusion, this study demonstrates that Phe exposure is positively associated with hyperuricemia and intestinal damage, which provides new insights into the toxic effects induced by Phe. Furthermore, the present study proposes that supplementation with TB would be a healthy and effective improvement strategy for patients with hyperuricemia and intestinal injury caused by environmental factors.

Induction of insulin resistance in female mice due to prolonged phenanthrene exposure: Unveiling the low-dose effect and potential mechanisms

Phenanthrene (Phe) is a commonly occurring polycyclic aromatic hydrocarbon (PAH) found in various food sources and drinking water. Previous studies have shown that long-term exposure to Phe in male mice leads to insulin resistance in a dose-dependent manner. However, the effect of Phe on glucose homeostasis in female mice remains unknown. To address this knowledge gap, female Kunming mice were exposed to Phe through their drinking water at concentrations of 0.05, 0.5, and 5 ng/mL. After 270 d of exposure, we surprisingly discovered a low-dose effect of Phe on insulin resistance in female mice, which differed from the effect observed in male mice and showed sexual dimorphism. Specifically, insulin resistance was only observed in the 0.05 ng/mL treatment, and this low-dose effect was also reflected in the concentration of Phe in white adipose tissue (WAT). Differences in metabolic enzyme activities in the liver may potentially explain this effect. The observed sexual dimorphism in Phe exposure could be attributed to variations in estrogen (E2) level and estrogen receptor beta (ERβ) expression in WAT. These findings highlight the association between environmental factors and the development of insulin resistance, emphasizing the pathogenic effect of even low doses of Phe. Moreover, sex dependent-effect should be given more attention when studying the toxic effects of environmental pollutants.

Oral exposure to phenanthrene during gestation disorders endocrine and spermatogenesis in F1 adult male mice

Phenanthrene (Phe), a typical low-molecular-weight polycyclic aromatic hydrocarbon (PAH) of three benzene rings, is one of the most abundant PAHs detected in daily diets. Pregnant women and infants are at great risk of Phe exposure. In the present study, Phe was administered to pregnant mice at a dose of 0, 60, or 600 μg/kg body weight six times, and the F1 male mice showed significant reproductive disorders: the testicular weight and testis somatic index were significantly reduced; the levels of serum testosterone, GnRH and SHBG were increased, while the FSH levels were reduced; histological analysis showed that the amount of Sertoli cells and primary spermatocytes in seminiferous tubules was increased, while the amount of secondary spermatocytes and spermatids were decreased in Phe groups. The protein levels of PCNA and androgen receptor were reduced. Differently expressed genes in the testis screened by RNA sequence were enriched in antioxidant capacity, reproduction et al.. Further biochemical tests confirmed that the antioxidant capacity in the F1 testis was significantly inhibited by treatment with Phe during pregnancy. Those results suggested that gestational Phe exposure disordered hypothalamic-pituitary-gonadal (HPG) hormones on the one hand, and on the other hand reduced testicular antioxidant capacity and further arrested cell cycle in F1 adult male mice, which co-caused the inhibition of spermatogenesis.

Biotransformation and toxicokinetics of 2-phenoxyethanol after oral exposure in humans: a volunteer study

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with tmax-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.

Effects of microplastics and phenanthrene on gut microbiome and metabolome alterations in the marine medaka Oryzias melastigma

Plastic pollution of the oceans is increasing, and toxic interactions between microplastics (MPs) and organic pollutants have become a major environmental concern. However, the combined effects of organic pollutants and MPs on microbiomes and metabolomes have not been studied extensively. In the present study, to evaluate whether MPs and phenanthrene (Phe) act synergistically in the guts of marine medaka (Oryzias melastigma), we performed toxicity assessments, 16 S rRNA gene sequencing, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. Our investigations revealed increased toxicity induced by Phe, as well as disturbances in gut microbiota (known as dysbiosis) when MPs were present. Furthermore, combined exposure to Phe and MPs resulted in greater alterations to microbiota composition and metabolite profiles. Notably, MP exposure was distinctly associated with the abundance of Shewanella and Spongiibacteraceae, while Phe exposure was associated with the abundance of Marimicrobium. Among key microbiota, Marimicrobium and Roseibacillus were significantly correlated with metabolites responsible for coenzyme A and glycerophospholipid metabolism in medaka. These results suggest that interactions between Phe and MPs may have significant effects on the gut microbiota and metabolism of aquatic organisms and underscore the importance of acknowledging the interplay between MPs and contaminants in aquatic environments.

Cardiac toxicity of phenanthrene depends on developmental stage in Atlantic cod (Gadus morhua)

Complex mixtures like crude oil, and single components such as Phenanthrene (Phe), induce cardiotoxicity by interfering with excitation-contraction coupling. However, recent work has demonstrated that the timing of pollutant exposure during embryogenesis greatly impacts the degree of cardiac dysfunction caused. Here, we aimed to clarify the temporal dependence of Phe toxicity and the downstream effects of cardiac dysfunction using Atlantic cod (Gadus morhua). Phe (nominal concentration, 1.12 μmol/L), or the L-type‑calcium channel blocker Nicardipine (Nic) (nominal concentration, 2 and 4 μmol/L), were individually applied to cod embryos either during cardiogenesis (early) or after the onset of cardiac function (late). Phe toxicity was highly dependent on the timing of exposure. Exposure after the onset of cardiac function (i.e. late) caused more severe cardiac and extracardiac abnormalities at 3 days post hatching (dph) than early exposure. Late Phe exposure resulted in a smaller ventricle, eliminated ventricular contraction, and reduced atrial contraction. In contrast, early Phe exposure did not have an effect on cardiac development and function. This temporal difference was not as evident in the Nic treatment. Early Nic exposure created similar morphological phenotypes to the late Phe exposure. The two treatments (early Nic and late Phe) also shared a cardiofunctional phenotype, comprised of eliminated ventricular, and reduced atrial, contraction. These data suggest that extracardiac abnormalities, such as the craniofacial deformities seen after late embryonic exposure to cardiotoxic oil components and mixtures, are mostly downstream effects of cardiac dysfunction.

The hepatoprotective effects of Herbt Tea Essences on phenanthrene-induced liver damage in mice

Phenanthrene (Phe), one of the most frequently occurring pollutants in nature, can cause substantial damage to the human liver. Herbt Tea Essences (HTE), a kind of black tea extract with strong anti-inflammatory activity, can protect humans against disease. Currently, whether HTE can protect the liver from Phe-induced hepatotoxicity remains unclear. Herein, we explore the protective effects of HTE against Phe-induced hepatotoxicity. Our results showed that Phe exposure could significantly induce liver damage and increase serum hepatic enzyme levels in mice. HTE could prevent liver damage and recover the expression levels of inflammatory factors. Furthermore, we found that HTE suppressed the excessive activation of the nuclear transcription factor kappa-B and transforming growth factor-β/SMAD signaling pathways to alleviate Phe-induced liver inflammation and fibrosis. Overall, our data showed that HTE treatment could be a new preventive means for Phe-induced liver disease.

Exposure of embryos to phenanthrene impacts the cardiac development in F1 zebrafish larvae and potential reasons.

To explore the impact of embryonic exposure to phenanthrene (Phe), a typical tricyclic polycyclic aromatic hydrocarbon, on cardiac development in next generation, fertilized zebrafish embryos were exposed to 0.05, 0.5, 5 and 50nM Phe for 96h, and then transferred to clear water and raised to adulthood. The cardiac development in F1 larvae generated by adult females or males mated with unexposed zebrafish was assessed. Malformation and dysfunction of the heart, such as increased heart rate, arrhythmia, enlarged heart and abnormal contraction, were shown in both paternal and maternal F1 larvae. A greater impact on the distance between the sinus venosus and bulbus arteriosus was exhibited in maternal F1 larvae, while paternal F1 larvae displayed a more severe impact on heart rate and arrhythmia. The transcription of genes related to cardiac development was disturbed in F1 larvae. DNA methylation levels in the promoter of some genes were associated with their transcription. The expression of acetylated histone H3K9Ac and H3K14Ac in maternal F1 larvae was no significantly changed, but was significantly downregulated in paternal F1 larvae, which might be associated with the downregulated transcription of tbx5. These results indicate that exposure to Phe during embryogenesis adversely affects cardiac development in F1 generation, and the effects and toxic mechanisms showed sex-linked hereditary differences, highlighting the risk of Phe exposure in early life to heart health in next generation.

Mechanistic insights into phenanthrene-triggered oxidative stress-associated neurotoxicity, genotoxicity, and behavioral disturbances toward the brandling worm (Eisenia fetida) brain: The need for an ecotoxicological evaluation

In this study, earthworm (Eisenia fetida) brain was chosen as targeted receptors to probe the mechanisms of oxidative stress-related neurotoxicity, genotoxicity, and behavioral disturbances triggered by PHE. Results showed that PHE stress can initiate significant amounts of ROS, thus triggering oxidative stress in E. fetida brain. These effects were accompanied by a significant increase of damage to macromolecules DNA and lipids, resulting in severe oxidative effects. PHE exposure can induce AChE inhibition by ROS-induced injury and the accumulation of excess ACh at the nicotinic post-synaptic membrane, thus inducing aggravated neurological dysfunction and neurotoxicity of E. fetida through an oxidative stress pathway. Moreover, the burrowing behavior of earthworms was disturbed by oxidative stress-induced neurotoxicity after exposure to PHE. Furthermore, the abnormal mRNA expression profiles of oxidative stress- and neurotoxicity-related genes in worm brain were induced by PHE stress. The IBR results suggested that E. fetida brain was suffered more serious damage caused by PHE under higher doses and long-term exposure. Taken together, PHE exposure can trigger oxidative stress-mediated neurotoxicity and genotoxicity in worm brain and behavioral disorder through ROS-induced damage. This study is of great significance to evaluate the harmful effects of PHE and its mechanisms on soil ecological health.

Effects of phenanthrene on the essential oil composition and leaf metabolome in peppermint plants (Mentha piperita L.)

Polycyclic aromatic hydrocarbons (PAHs) are an important type of persistent organic pollutant that endangers soil ecosystems and human health. Cultivating aromatic plants in PAH-contaminated soils is considered a safe and sustainable phytoremediation strategy to mitigate PAH soil pollution. However, the impact of PAHs on plant essential oils and the metabolic responses within aromatic plants remain unclear. In this study, we investigated the effects of the model PAH phenanthrene (Phe) on the chemical composition of essential oils in the ubiquitous aromatic plant peppermint (Mentha piperita L.) using gas chromatography-mass spectrometry (GC-MS). A total of 56 essential oil components were identified in the plants, among which the ratios of 21 components were significantly altered by Phe exposure. However, the fundamental components of peppermint essential oils including menthol, menthone, menthofuran, and pulegone did not exhibit considerable changes in levels. Thus, Phe stress may have little effect on the primary characteristics of peppermint essential oils. We also evaluated the effects of Phe treatment on metabolome dynamics within peppermint leaves by detecting metabolites in leaves treated with Phe for 0, 1, 3, 5, and 7 days (d) using non-targeted metabolomics. Compared with their corresponding control groups, 26 key different metabolites in the Phe-treated groups were identified and annotated via enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Enriched metabolites were primarily involved in the oxidation of unsaturated fatty acids (UFAs), phenylpropanoid metabolism, amino acids, and the formation of vitamin C and caffeine. Phe treatment significantly promoted the oxidation of UFAs, phenylpropanoid metabolism, and histidine production in the first three days of Phe treatment. After 3 d, Phe gradually suppressed the oxidation of UFAs and L-glutamic acid production, while promoting phenylpropanoid metabolism, in addition to the synthesis of vitamin C and caffeine. The dynamic changes in metabolic pathway functioning in Phe-treated peppermint leaves reveal adaptive defensive mechanisms to mitigate Phe stress. This study provides new insights into the responses of aromatic plants toward PAH stress, while also providing a reference for the application of aromatic plants in the phytoremediation of PAH-contaminated soils.

Hibiscus sabdariffa Extract Protects HaCaT Cells against Phenanthrene-Induced Toxicity through the Regulation of Constitutive Androstane Receptor/Pregnane X Receptor Pathway.

Phenanthrene (Phe) exposure is associated with skin ageing, cardiotoxicity and developmental defects. Here, we investigated the mode of Phe toxicity in human keratinocytes (HaCaT cells) and the attenuation of toxicity on pre-treatment (6 h) with ethanol extract of Hibiscus sabdariffa calyxes (HS). Cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm) alteration, changes in the transcriptional activity of selected genes involved in phase I and II metabolism, antioxidant response and gluconeogenesis, western blot and docking studies were performed to determine the protective effect of HS against Phe. Phe (250 μM) induced cytotoxicity in HaCaT cells through AhR-independent, CAR/PXR/RXR-mediated activation of CYP1A1 and the subsequent alterations in phase I and II metabolism genes. Further, CYP1A1 activation by Phe induced ROS generation, reduced ΔΨm and modulated antioxidant response, phase II metabolism and gluconeogenesis-related gene expression. However, pre-treatment with HS extract restored the pathological changes observed upon Phe exposure through CYP1A1 inhibition. Docking studies showed the site-specific activation of PXR and CAR by Phe and inhibition of CYP1A1 and CYP3A4 by the bioactive compounds of HS similar to that of the positive controls tested. Our results conclude that HS extract can attenuate Phe-induced toxicity in HaCaT cells through CAR/PXR/RXR mediated inhibition of CYP1A1.

Phenanthrene induces autism-like behavior by promoting oxidative stress and mTOR pathway activation

Autism is thought to be associated with both environmental and genetic factors. Phenanthrene (Phe) makes up a relatively high proportion of the low-ring polycyclic aromatic hydrocarbons. However, the association between exposure to Phe and Autism remain unclear. In this study, the effect and mechanisms of phenanthrene exposure on autistic behavior were investigated. Three-week-old male Kunming mice were exposed to doses of 5, 50, or 500 μg/kg/d Phe for 22 days. Exposure to phenanthrene induced a marked decrease in the activity of the mice in the central area in the open field test, and caused a significant decrease in communication with unfamiliar mice in the three-chambered social test. The hippocampus of the mice exposed to high concentrations of Phe showed pathological changes. Exposure to phenanthrene induced an increase in the levels of ROS and a decrease in levels of glutathione, and caused a significant decrease in the expression of Shank3 and Beclin1. This also led to an increase in the phosphorylation levels of Akt and mTOR. However, administering Rapamycin or vitamin E, inhibited the oxidative stress and activation of the mTOR pathway induced by Phe exposure, effectively alleviating the above-mentioned autistic-like anxious social behaviors. These results indicate that exposure to phenanthrene will lead to autism-like behavior. The underlying mechanism involves oxidative stress and the mTOR pathway.

Cardiac dysfunction affects eye development and vision by reducing supply of lipids in fish

Developing organisms are especially vulnerable to environmental stressors. Crude oil exposure in early life stages of fish result in multiple functional and developmental defects, including cardiac dysfunction and abnormal and smaller eyes. Phenanthrene (Phe) has a reversible impact on cardiac function, and under exposure Phe reduces cardiac contractility. Exposure to a known L-type channel blocker, nicardipine hydrochloride (Nic) also disrupts cardiac function and creates eye deformities. We aimed to investigate whether cardiac dysfunction was the major underlying mechanism of crude oil-, Phe- and Nic-induced eye malformations. We exposed Atlantic haddock (Melanogrammus aeglefinus) early embryos to Nic and crude oil (Oil) and late embryos/early larvae to Phe exposure. All three exposures resulted in cardiac abnormalities and lead to severe, eye, jaw and spinal deformities at early larval stages. At 3 days post hatching, larvae from the exposures and corresponding controls were dissected. Eyes, trunk, head and yolk sac were subjected to lipid profiling, and eyes were also subjected to transcriptomic profiling. Among most enriched pathways in the eye transcriptomes were fatty acid metabolism, calcium signaling and phototransduction. Changes in lipid profiles and the transcriptome suggested that the dysfunctional and abnormal eyes in our exposures were due to both disruption of signaling pathways and insufficient supply of essential fatty acids and other nutrients form the yolk.

Acute and chronic toxicity of microcystin-LR and phenanthrene alone or in combination to the cladoceran (Daphnia magna)

Hazardous substances, such as microcystin-LR (MC-LR) and phenanthrene (Phe) are ubiquitous co-contaminants in eutrophic freshwaters, which cause harms to aquatic organisms. However, the risks associated with the co-exposure of aquatic biota to these two chemicals in the environment have received little attention. In this study, the single and mixture toxic effects of MC-LR and Phe mixtures were investigated in Daphnia magna after acute and chronic exposure. Acute tests showed that the median effective concentrations (48 h) for MC-LR, Phe and their mixtures were 13.46, 0.57 and 8.84 mg/L, respectively. Mixture toxicity prediction results indicated that the independent action model was more applicable than the concentration addition model. Moreover, combination index method suggested that the mixture toxicity was concentration dependent. Synergism was elicited at low concentrations of MC-LR and Phe exposure (≤4.04 + 0.17 mg/L), whereas antagonistic or additive effects were induced at higher concentrations. The involved mechanism of antagonism was presumably attributable to the protective effects of detoxification genes activated by high concentrations of MC-LR in mixtures. Additionally, chronic results also showed that exposure to a MC-LR and Phe mixture at low concentrations (≤50 +2 μg/L) resulted in greater toxic effects on D. magna life history than either chemical acting alone. The significant inhibition on detoxification genes and increased accumulation of MC-LR could be accounted for their synergistic toxic effects on D. magna. Our findings revealed the exacerbated ecological hazard of MC-LR and Phe at environmental concentrations (≤50 +2 μg/L), and provided new insights to the potential toxic mechanisms of MC-LR and Phe in aquatic animals.

Long-term exposure to environmental levels of phenanthrene disrupts spermatogenesis in male mice

Phenanthrene (Phe) is a tricyclic polycyclic aromatic hydrocarbon with high bioavailability under natural exposure. However, there are few studies on the reproductive toxicity of Phe in mammals. In this study, male Kunming mice were gavaged once every two days with Phe (5, 50, and 500 ng/kg) for 28 weeks. The accumulation levels of Phe in the testis were dose-dependently increased. Histopathological staining showed that Phe exposure reduced the number of spermatogonia, sperm and Sertoli cells. The percentage of testicular apoptotic cells was significantly increased, which was further verified by the upregulated BAX protein. The expression of the GDNF/PI3K/AKT signaling pathway was downregulated, which might suppress the self-renewal and differentiation of spermatogonial stem cells. Meanwhile, Phe exposure inhibited the expression of Sertoli cell markers (Fshr, WT1, Sox9) and the Leydig cell marker Cyp11a1, indicating damage to the function of Sertoli cells and Leydig cells. Serum estrogen and testicular estrogen receptor alpha were significantly upregulated, while androgen receptor expression was downregulated. These alterations might be responsible for impaired spermatogenesis. This study provides new insights for evaluating the reproductive toxicity and potential mechanisms of Phe in mammals.

Long-term exposure to environmental level of phenanthrene causes adaptive immune response and fibrosis in mouse kidneys

As ubiquitous, persistent organic pollutants, polycyclic aromatic hydrocarbons (PAHs) have adverse impacts on human health. Phenanthrene (Phe) is one of the most abundant PAHs in the environment. However, the long-term effects of exposure to environmental level of Phe on the kidneys and the potential mechanisms are unclear. T helper (Th) cells, a subtype of CD4+ T cells that play a central role in the renal immune microenvironment. In this study, male mice were chronically exposed to 5, 50, and 500 ng/kg bw Phe every other day for total 210 days. Those results indicated that environmental Phe exposure caused kidney hypertrophy, injury and fibrosis in the mice. Chronic, long-term environmental level of Phe exposure did not significantly alter the innate immune response but induced adaptive immune response changes (Th1/Th2 related cytokines release), causing a type 1 immune response in the 5 ng/kg bw Phe group and a type 2 immune response in the high dose groups (50 and 500 ng/kg bw). This study provides novel insights into the roles of adaptive immune response in long-term PAH exposure-induced chronic kidney injury and fibrosis, which is beneficial for further understanding the potential health hazards of PAHs and providing new avenues for immune intervention strategies to alleviate PAHs toxicity.

Transcriptome changes of Takifugu obscurus liver after acute exposure to phenanthrene.

Phenanthrene (Phe) is a model compound in polycyclic aromatic hydrocarbon (PAH) research. Reportedly, Phe treatment induced oxidative stress and histological disorders to Takifugu obscurus liver. In this study, to further explore the molecular responses of T. obscurus liver to Phe exposure, transcriptome sequencing was applied to compare mRNA transcription profiles between Phe treatment and the control. Compared with the control, 1,581 and 1,428 genes were significantly upregulated and downregulated in Phe treatment, respectively. Further analysis revealed that Phe treatment mainly upregulated genes in Ras-MAPK and PI3K-akt signaling pathways, which represented insulin resistance and further activated the FOXO signaling pathway. The triacylglycerol biosynthesis was promoted but the gluconeogenesis process was inhibited in response to Phe treatment, demonstrating that Phe exposure disturbed the sugar and lipid metabolism. Moreover, Phe treatment upregulated the Apelin-APJ and ErbB signaling pathways, promoting angiogenesis in T. obscurus liver. Insulin resistance, promoted triacylglycerol biosynthesis, and angiogenesis might explain the molecular mechanisms underlying carcinogenic toxicity of Phe. Overall, this study provides new insights to understand the environmental risk of Phe to fishes.