Search

Molybdenum disulphide (MoS2) is a constituent of many products. To protect humans, it is important to know at what air concentrations it becomes toxic. For this, we tested MoS2 particles by nose-only inhalation in mice. Exposures were set to 13, 50 and 150 mg MoS2/m3 (=8, 30 and 90 mg Mo/m3), corresponding to Low, Mid and High exposure. The duration was 30 min/day, 5 days/week for 3 weeks. Molybdenum lung-deposition levels were estimated based on aerosol particle size distribution measurements, and empirically determined with inductively coupled plasma-mass spectrometry (ICP-MS). Toxicological endpoints were body weight gain, respiratory function, pulmonary inflammation, histopathology, and genotoxicity (comet assay). Acellular reactive oxygen species (ROS) production was also determined. The aerosolised MoS2 powder had a mean aerodynamic diameter of 800 nm, and a specific surface area of 8.96 m2/g. Alveolar deposition of MoS2 in lung was estimated at 7, 27 and 79 µg/mouse and measured as 35, 101 and 171 µg/mouse for Low, Mid and High exposure, respectively. Body weight gain was lower than in controls at Mid and High exposure. The tidal volume was decreased with Low and Mid exposure on day 15. Increased genotoxicity was seen in bronchoalveolar lavage (BAL) fluid cells at Mid and High exposures. ROS production was substantially lower than for carbon black nanoparticles used as bench-mark, when normalised by mass. Yet if ROS of MoS2 was normalised by surface area, it was similar to that of carbon black, suggesting that a ROS contribution to the observed genotoxicity cannot be ruled out. In conclusion, effects on body weight gain and genotoxicity indicated that Low exposure (13 mg MoS2/m3, corresponding to 0.8 mg/m3 for an 8-hour working day) was a No Observed Adverse Effect Concentration (NOAEC,) while effects on respiratory function suggested this level as a Lowest Observed Adverse Effect Concentration (LOAEC). Molybdenum disulphide (MoS2) is a constituent of many products. To protect humans, it is important to know at what air concentrations it becomes toxic. For this, we tested MoS2 particles by nose-only inhalation in mice. Exposures were set to 13, 50 and 150 mg MoS2/m3 (=8, 30 and 90 mg Mo/m3), corresponding to Low, Mid and High exposure. The duration was 30 min/day, 5 days/week for 3 weeks. Molybdenum lung-deposition levels were estimated based on aerosol particle size distribution measurements, and empirically determined with inductively coupled plasma-mass spectrometry (ICP-MS). Toxicological endpoints were body weight gain, respiratory function, pulmonary inflammation, histopathology, and genotoxicity (comet assay). Acellular reactive oxygen species (ROS) production was also determined. The aerosolised MoS2 powder had a mean aerodynamic diameter of 800 nm, and a specific surface area of 8.96 m2/g. Alveolar deposition of MoS2 in lung was estimated at 7, 27 and 79 µg/mouse and measured as 35, 101 and 171 µg/mouse for Low, Mid and High exposure, respectively. Body weight gain was lower than in controls at Mid and High exposure. The tidal volume was decreased with Low and Mid exposure on day 15. Increased genotoxicity was seen in bronchoalveolar lavage (BAL) fluid cells at Mid and High exposures. ROS production was substantially lower than for carbon black nanoparticles used as bench-mark, when normalised by mass. Yet if ROS of MoS2 was normalised by surface area, it was similar to that of carbon black, suggesting that a ROS contribution to the observed genotoxicity cannot be ruled out. In conclusion, effects on body weight gain and genotoxicity indicated that Low exposure (13 mg MoS2/m3, corresponding to 0.8 mg/m3 for an 8-hour working day) was a No Observed Adverse Effect Concentration (NOAEC,) while effects on respiratory function suggested this level as a Lowest Observed Adverse Effect Concentration (LOAEC).

Background Silica nanoparticles (SiNPs) are widely used as drug carriers for improving drug delivery and retention. The lungs are highly sensitive to toxicity of SiNPs entering the respiratory tract. Furthermore, pulmonary lymphangiogenesis, which is the growth of lymphatic vessels observed during multiple pulmonary diseases, plays a vital role in promoting the lymphatic transport of silica in the lungs. However, more research is required on the effects of SiNPs on pulmonary lymphangiogenesis. We investigated the effect of SiNPs-induced pulmonary toxicity on lymphatic vessel formation in rats and evaluated the toxicity and possible molecular mechanisms of 20-nm SiNPs. Female Wistar rats were instilled intratracheally with saline containing 3.0, 6.0, and 12.0 mg/kg of SiNPs once a day for 5 days, then sacrificed on day 7. Lung histopathology, pulmonary permeability, pulmonary lymphatic vessel density changes, and the ultrastructure of the lymph trunk were investigated using light microscopy, spectrophotometry, immunofluorescence, and transmission electron microscopy. CD45 expression in lung tissues was determined using immunohistochemical staining, and protein expression in the lung and lymph trunk was quantified using western blotting. Results We observed increased pulmonary inflammation and permeability, lymphatic endothelial cell damage, pulmonary lymphangiogenesis, and remodeling with increasing SiNPs concentration. Moreover, SiNPs activated the VEGFC/D–VEGFR3 signaling pathway in the lung and lymphatic vessel tissues. Conclusions SiNPs result in inflammation-associated lymphangiogenesis and remodeling, further pulmonary damage, and increased permeability by activating VEGFC/D–VEGFR3 signaling. Our findings provide evidence for SiNPs-induced pulmonary damage and a new perspective for the prevention and treatment of occupational exposure to SiNPs.

Hydrogen sulfide (H

A great variety of endocrine-disrupting chemicals (EDCs) have been used extensively and become widespread in the environment nowadays. Limited mammalian studies have shown that certain EDCs may target chromosome and epigenome of the germline, leading to adverse effects in subsequent generations, despite these progenies having never been exposed to the EDC before. However, the underlying mechanisms of chromosomal changes induced by these pollutants remain poorly known. Using the human ovarian granulosa tumor cell line COV434 as a model, we investigated and compared the transcriptomic changes induced by nine EDCs with diverse chemical structures (i.e. BDE-47, BPA, BP-3, DEHP, DHP, EE2, TCS, TDCPP and NP), to inquire if there is any common epigenetic modification associated with reproductive functions induced by these EDCs. Our results showed that COV434 cells were more responsive to BP-3, NP, DEHP and EE2, and more importantly, these four EDCs altered the expression of gene clusters related to DNA damage response, cell cycle, proliferation, and chromatin remodeling, which can potentially lead to epigenetic modifications and transgenerational inheritance. Furthermore, dysregulation of similar gene clusters was common in DEHP and NP treatments. Bioinformatics analysis further revealed that BP-3 disturbed signaling pathways associated with reproductive functions, whereas alterations in telomere-related pathways were highlighted upon EE2 exposure. Overall, this study highlighted chromatin modifications caused by a class of chemicals which that may potentially lead to epigenetic changes and transgenerational reproductive impairments.

Human exposure to plastic contaminated foods and environmental micro/nano plastic derived chemicals necessitates system-wide health risk assessment. Hence, current study intend to explore the mode of action (MoA) based adverse outcome pathways of 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the major active metabolite of bisphenol A (BPA). The computational study employed broad range of target prediction, systems biology tools and molecular docking protocols. Further, validation of MBP targets was done using protein-ligand fluorescence quenching assay, endothelial cell culture and chicken embryo vascular angiogenesis models. Interestingly, the current results illustrate that various physiological signaling pathways (MAPK and VEGF related angiogenesis signaling) and disease progression pathways (hypertension, cancer and endocrine disorders) were enriched as potential targets of MBP. Further, docking studies highlights the possible binding mechanism of MBP with important targets including endothelial nitric oxide synthase (eNOS) and serum albumin (BSA). In addition, the validation studies on MBP-BSA interaction (fluorescence quenching), eNOS derived nitric oxide (NOx) generation in endothelial cells and chicken embryo angiogenesis support the system-wide impacts of MBP with highlights on cardiovascular pathogenesis. Thus, the current observation provides novel insights into the system wide impacts of MBP for the futuristic health risk assessment of plastic derived chemicals.

Numerous studies have shown that exposure to micro- or nano-plastics led to the cell viability and function of macrophages in the intestine tissue might be one possible mechanism. This study investigated the cytotoxicity and pro-inflammatory effect of 80 nm polystyrene-nano-plastic (PS-NP) and 3 µm PS-micro-plastic (PS-MP) on mouse macrophages RAW264.7 cells. Our results showed that exposure to PS-NP or PS-MP induced apoptosis of cells at 5 or 10 μg/mL, respectively. Besides, PS-NP enhanced the secretion of inflammatory cytokines (Tumor necrosis factor-α, Interleukin-6 and Interleukin-10) with the lowest effective concentration (LOEC) of 1, 0.01, and 0.01 μg/mL, respectively. PS-MP enhanced secretion of TNF-α and IL-10 with the LOEC of 1 and 0.01 μg/mL, respectively. We further studied the possible mechanisms of the effects of PS-NP or PS-MP on RAW264.7 cells. We found they might cause cytotoxicity and inflammatory effects by producing reactive oxygen species and nitric oxide in the cells. Accordingly, our results demonstrated that PS-NP and PS-MP had cytotoxicity and pro-inflammatory effect on macrophages, which might further lead to intestinal inflammation. Moreover, we revealed that the PS-NP had more potent adverse impacts on macrophages than PS-MP.

Microplastic in the environment have the capability to reach the human immune system via the ingestion, inhalation and direct contact. Polystyrene (PS) is one of the most widely used plastics, which is made up by polymerization of styrene monomers. Mounting evidences on the presence of microplastics in blood clearly indicate their access to macrophages that are major component of the immune system. However, data on the response of macrophages to microplastics exposure are limited. Our study reports the response of human macrophages transformed by PMA (phorbol 12-myristrate 13-acetate) to exposure to PSNPs of size range (≤ 450 nm). The polystyrene particles utilized in this study, were formulated from beads to powder by grinding and filtering the particles to acquire a range of size ≤ 450 nm particles with deionized water. This size variation used in this experiment imitates the size of plastic that humans can ingest plastic particles through food that gets fragmented from plastic cups and plates. Here we report that exposure to PSNPs (50-500 µg/mL) significantly decreased the viability of human macrophages. In addition, PSNPs (500 µg/mL) induced oxidative stress and decrease cell proliferation. Exposure to PSNPs decrease the membrane potential of mitochondria and caused damage to the DNA of macrophages. Overall, our study reports the differential toxic effects of PSNPs on human macrophages, delineating the potential risks of PSNPs exposure to human health.

To investigate the potential factors of graphene quantum dots (GQDs), the assessment impact on the innate immune system is one of the most important. As the innate immune cell, macrophages possess phagocytosis activity and affect immunomodulation. Higher oxygen consumption rates (OCR) are used to gain insight into GQDs' effects on macrophages. Metabolomics profiling also revealed that GQDs exposure provoked an increase in phosphoglycerides, sphingolipids, and oxidized lipids in macrophages. The molecular pathways disrupted by GQDs were associated with lipid and energy metabolisms. Metabolite flux analysis was used to evaluate changes in the lipid metabolism of macrophages exposed to 100 µg mL

Ataxia telangiectasia mutated (ATM) is a pivotal sensor during the DNA damage response that slows cell passage through the cell cycle checkpoints to facilitate DNA repair, and liver fibrosis is an irreversible pathological consequence of the sustained wound-healing process, However, the effects of ATM on the development of liver fibrosis are still not fully understood. Therefore, the aim of the study was to investigate the effects and potential mechanisms of ATM on the progression of liver fibrosis. Wild-type and ATM-deficient were administered with carbon tetrachloride (CCl

Mercury (Hg) is harmful to the environment and human health. The gut plays important roles as the biological, chemical, mechanical, and immune barriers in animals and human beings. It has been known that Hg can be absorbed and methylated/demethylated in the gut, on the other hand, the impacts of Hg to the gut (especially the gut microbiota) is less studied. This review paper summarizes the impacts of inorganic Hg (IHg) and methyl Hg (MeHg) on gut barriers and the extraintestinal effects (damage to other organs such as the liver and brain). Both IHg and MeHg were found to cause intestinal microbial disorders, abnormal metabolites production, tight junction damage, and immune responses in the gut. The damage to the gut also contributed to the extraintestinal effects like the hepatotoxicity by IHg and the neurotoxicity by MeHg. In all, it is proposed that the gut should be considered as an important target tissue of Hg exposure, and the regulation of gut microbiota may have the potential for the prevention and control of the toxicity of Hg.

Sulfur mustard (SM), an extremely reactive alkylating toxicant, which poses a continuing threat to both military and civilian populations. SM targets three major organs including skin, eyes and lungs. In recent years, more and more clinical findings have shown that cognitive and emotional disorders in veterans intoxicated with SM, such as anxiety, depression, apathy, cognitive decline and so on, which indicated the long time toxic effects on mental and neurological health of SM. The experimental studies in animal and cell models have also found neurotoxicity which are similar to clinical results. However, these neuropsychological problems are not studied well in victims of SM and the mental and neurological complications are often not subjected to treatment or undertreated. Until now, the exact mechanism of the action of SM toxicity has not been elucidated and no specific therapy for its poisoning exists. Therefore, the studies on neurotoxicity of SM should be strengthened. This review summarizes the main progress of clinical and experimental researches on neurotoxicity of SM for the past few years.

As the use of bisphenol A (BPA) has been restricted in consumer products, bisphenol S (BPS) is one major alternative to BPA for various materials, leading to growing concerns about its health risks in human beings. However, little is known about the toxic effects of BPS on bone health. We employed human bone marrow mesenchymal stem cells (hBMSCs) for the in vitro assessment of BPS on cell proliferation, differentiation, and self-renewal. Our study revealed that BPS at concentrations of 10

There is evidence of an association between exposure to ambient fine particulate matter (PM2.5) and female ovarian dysfunction in adults. However, it is not fully clear whether maternal exposure to PM2.5 negatively affects the ovarian function in offspring. The size of primordial follicle pool, definitely assembled during fetal life, determines ovarian reserve and ovarian function. In this study, female C57BL/6 mice were exposed to either ambient PM2.5 (mean daily concentration 49 µg/m

Cyadox, a potential antimicrobial growth promoter, has been widely studied and prospected to be used as an additive in livestock and poultry feed. Although high cyadox exposure has been reported to cause toxicity, the exact metabolic effects are not fully understood. Our study aim is to evaluate the metabolic effects of cyadox using comprehensive methods including serum clinical chemical test, histopathology analysis, metabolomics, and transcriptomics profile analysis. One single acute dosage over 7-day course and one subchronic 90-day dietary ingestion of cyadox intervention were conducted on the Wistar rats separately. Dose-dependent alterations were shown in the metabolism of the urine, kidney, plasma, and liver by metabolomics analysis. We further investigated gene expressions of the liver administered with high dose of cyadox for 12 weeks. Top sixty-six differentially expressed genes involved in the pathways, including xenobiotic (cyadox) metabolism, lipid metabolism, energy metabolism, nucleic acid metabolic process, inflammatory response, and response to the oxidative stress, which were in concordance with these metabolic alternations. Our study provided a comprehensive information on how cyadox modulates the metabolism and gene expressions, which is vital when considering the safe application of cyadox.

The existence of a complex hormonal balance among glucocorticoids, androgens and estrogens involved in the regulation of Receptor for Activated C Kinase 1 (RACK1) expression and its related immune cells activation, highlights the possibility to employ this protein as screening tool for the evaluation of the immunotoxic profile of endocrine disrupting chemicals (EDCs), hormone-active substances capable of interfering with the physiologic hormonal signaling. Hence, the aim of this work was to investigate the effect of the exposure of EDCS 17α-ethynylestradiol (EE), diethyl phthalate (DEP) and perfluorooctanesulfonic acid (PFOS) on RACK1 expression and on lipopolysaccharide (LPS)-induced activation of the human monocytic cell line THP-1, a validated model for this investigation. In line with our previous results with estrogen-active compounds, EE treatment significantly induced RACK1 promoter transcriptional activity, mRNA expression, and protein levels, which paralleled an increase in LPS-induced IL-8, TNF-α production and CD86 expression, previously demonstrated to be dependent on RACK1/PKCβ activation. EE mediates its effect on RACK1 expression through G-protein-coupled estrogen receptor (GPER) and androgen receptor (AR) ligand-independent cascade, as also suggested by in silico molecular docking simulation. Conversely, DEP and PFOS induced a dose-dependent downregulation of RACK1 promoter transcriptional activity, mRNA expression, and protein levels, which was mirrored by a reduction of IL-8, TNF-α production and CD86 expression. Mifepristone pre-treatments abolish DEP and PFOS effects, confirming their GR agonist profile, also corroborated by molecular docking. Altogether, our data confirm that RACK1 represents an interesting target of steroid active compounds, which expression offers the opportunity to screen the immunotoxic potential of different hormone-active substances of concerns due to their human exposure and environmental persistence.

Paraquat (PQ) is a bipyridine herbicide and oral exposure is the main way of PQ exposure with a very high mortality. At present, it is believed that large number of oxygen free radicals are generated and cause lipid peroxidation of tissue and organ cell membranes after PQ is absorbed. PQ exposure could cause multiple organ dysfunction, among which acute lung injury is the most common and most serious. However, its specific mechanism is still unclear. In this study, the C57BL/6J mouse (alveolar epithelial cell-specific knockout HIF-1α) model of acute lung injury (40 mg/kg PQ) at several time pointes and a model of acute type II alveolar epithelial cell (A549, 800 μM PQ) injury constructed. The oxidative stress (ROS, MDA) and inflammatory response (IL-1β, IL-6, TNF-α) were significantly inhibited in the alveolar epithelial cell-specific knockout of HIF-1α mice and siRNA technology to inhibit HIF-1α in alveolar epithelial cells. Further proteomic analysis showed that the expression of Rac2 protein, which is closely related to oxidative stress, was significantly increased after PQ exposure. And the inhibition of Rac2 expression in vitro significantly alleviated PQ-induced oxidative stress and inflammatory response. The expression of Rac2 protein was regulated by HIF-1α. The above suggests that HIF-1α may promote oxidative stress and inflammatory response in alveolar epithelial cells by regulating the expression of Rac2, and then participate in the promotion of PQ exposure-induced acute lung injury.

Melatonin (MLT) was reported to have therapeutic effects on inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) due to its anti-inflammatory and immunomodulatory properties. However, whether the beneficial effects of melatonin on colitis are through altering the immune response of bone marrow-derived dendritic cells (BMDCs) has not been well characterized. Here, we propose that MLT alleviates dextran sulfate sodium (DSS)-induced colitis in mice through its regulation of the immune response of BMDCs, in which some lncRNA, circRNA, miRNA, and mRNA may be involved. We at first established a DSS-induced colitis mouse model and found that the concentration of MLT in the serum of DSS-induced colitis mice was significantly lower than that in the control mice. Supplementation with MLT alleviated DSS-induced colitis in mice, which was reflected by preventing mouse body weight loss, colon length shortening, inflammation, and epithelial tissue destruction and abscission in the colon. We then isolated and cultured BMDCs and found that MLT could inhibit the activation of BMDCs from the colitis mice, which was reflected by reducing the phagocytotic ability of the cells, inhibiting their migration, and decreasing their secretion of pro-inflammatory cytokines. RNA sequencing results showed that MLT promoted the transformation of BMDCs into immune tolerant phenotypes in DSS-induced colitis mice through affecting non-coding RNAs (ncRNAs). Among them, lncRNA ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miRNA-709, and mRNAs of Ywhaz and Ccl9 were the targets of miRNA-709, all of which were involved in MLT-induced alteration of BMDCs functions in DSS-induced colitis mice via PI3K-Akt pathway. Our findings may provide some clues for understanding MLT inhibiting inflammatory response in DSS-induced colitis, which may be through alteration of BMDCs function.

Polystyrene nanoplastics (PS NPs) contamination is a serious problem for human and animal health. Excessive exposure to PS NPs can affect the structure and function of the heart. And lipopolysaccharide (LPS) induces myocardial damage, leading to myocardial fibrosis (MF). To investigate whether PS NPs exacerbate LPS-induced myocardial autophagy and fibrosis, we established in vivo and in vitro models of PS NPs/LPS exposure alone and in combination. We found that PS NPs/LPS exposure disrupts myocardial structure, significantly increases reactive oxygen species (ROS), triggers oxidative stress, promotes TGF-β1/Smad pathway activation, and leads to elevated levels of fibrotic proteins and collagen. Meanwhile, activation of AMPK/mTOR/ULK1 signaling pathway induced autophagy onset, and combined exposure of PS NPs/LPS exacerbated MF and autophagy. H9C2 cells were used for in vitro experiments, and the experimental results showed that the addition of TGF-β receptor inhibitor LY2109761 to the exposed group not only inhibited the upregulation of fibrotic genes but also effectively reduced the expression of autophagic signals, indicating that combined exposure of PS NPs and LPS mediates and regulates cardiac autophagy through TGF-β1. The above results suggest that PS NPs exacerbate LPS-induced MF and autophagy in mice via ROS/TGF-β1/Smad. Our study provides some new evidence to clarify the potential mechanisms of PS NPs-induced cardiotoxicity.

β-N-Methyl-Amino-L-Alanine (BMAA) produced by 95% of cyanobacteria is in constant augmentation with cyanobacteria worldwide proliferation due to global warming and eutrophication. Previously, it has been shown that this contaminant induced neurological disorders, notably by acting as a developmental toxin. However, very few studies focus on the impact of BMAA on neuroglial cells, like astrocytes and microglial cells, in a developmental context. In the present study, we investigated whether BMAA disturbs neurogenesis from mice subventricular zone (SVZ) cells and whether this neurotoxin induces neuroinflammation. We show that BMAA at 100 µM disturbs the population of undifferentiated cells (B1 and C cells) and promotes their proliferation. Further, BMAA affects the organization of neuroblasts, indicating that SVZ function could be impaired. BMAA affects neuroinflammatory processes by increasing the release of proinflammatory cytokines IL-1β, IL-6 and TNFα. Our study adds to evidence that BMAA may disturb the central nervous system homeostasis by targeting glial cells. We highlighted that BMAA may impair SVZ niches and drives astrocytes and microglial cells into a proinflammatory status, with an ameboid shape for microglia.

To investigate the effect and mechanism of Pou4f3 gene mutation on pyroptosis in cochleae of cisplatin-induced deafness mice.Mice were intraperitoneally injected with cisplatin to construct an animal model of deafness, and sh-Pou4f3 and mutant vector were injected to alter gene expression. TUNEL staining was used to assess the apoptosis level of cochlear hair cells, ELISA was used to detect the secretion of inflammatory factors, and immunofluorescence and Western Blot were used to detect the expression of pyroptosis related factors.Cisplatin induced pyroptosis through NLRP3/Caspase-3/GSDME pathway and significantly down-regulated Pou4f3 level. Pou4f3 mutations promote cochlear hair cell pyroptosis by activating the NLRP3/Caspase-3/GSDME pathway. Knockdown of Pou4f3 can superimpose cisplatin treatment to induce pyroptosis of cochlear hair cells through NLRP3/Caspase-3/GSDME pathway.Pou4f3 gene mutation promotes pyroptosis of cochleae in cisplatin-induced deafness mice through NLRP3/Caspase-3/GSDME pathway.

Sorafenib (Sor), a novel multi-target anticancer drug also induces severe toxicity in heart, while the mechanism of its cardiotoxicity remains to be fully elucidated. Dysregulation of autophagy and mitochondrial dynamics imbalance have been implicated in cardiomyocyte death. The aim of this study is to test the hypothesis that Sor disrupts autophagy and mitochondrial dynamics, thereby aggravating Sor-induced oxidative stress damage to cardiomyocytes. Our results revealed that Sor (≥ 5 μM) concentration- and time-dependently reduced cell viability and induced apoptosis in H9c2 myoblasts. Sor treatment promoted intracellular reactive oxygen species (ROS) generation, and subsequent Ca

Perinatal and neonatal exposure to bisphenol A (BPA) has been linked to enhancement of prostate carcinogenesis in rats induced by combined treatment with estradiol and testosterone, but human data are lacking. This study aimed to determine the effects of perinatal BPA exposure on induction of prostate cancer in rats by sequential treatment with N-methyl-N-nitrosamine (MNU) and continuous low dose administration of testosterone. Pregnant Sprague Dawley rats were exposed to BPA administered by subcutaneous Alzet minipumps at doses of 2.5 or 25 µg/kg body weight/day from gestational day 9 until postnatal day 28 when pups were weaned providing exposure of offspring in utero and via the mother's milk. At 10-12 weeks of age, one male offspring per litter was treated with an intraperitoneal injection of MNU after hormonal stimulation of prostatic cell proliferation followed two weeks later by subcutaneous insertion of Silastic implants containing testosterone until the termination of the study 57-58 weeks after MNU injection. The perinatal BPA exposure did not significantly affect the incidence of prostate carcinomas which was slightly lower in exposed rats (33-23 %) than in control animals (40 %). Carcinomas in all accessory sex glands combined were also insignificantly less frequent in exposed (46-48 %) than in control rats (60 %). The incidence of malignant tumors at any site in the body was significantly lower in exposed rats (81-65 %) than in controls (93 %). In conclusion, perinatal BPA exposure did not significantly modify prostate cancer induction by MNU plus testosterone in rats, unlike the enhancement of prostate carcinogenesis induced by treatments involving estradiol administration. Which of the two models of prostate carcinogenesis is more relevant for the human situation is unclear at present.

Per- and polyfluoroalkyl substances (PFAS) are a family of man-made chemicals with currently over 4'700 compounds identified. While toxicological data are available for some of the legacy PFAS, such as PFOA and PFOS, a knowledge gap remains concerning both emerging and legacy PFAS' toxicity due to the diversity of the PFAS. Therefore, a better understanding of the PFAS structure-activity relationship may prove helpful. The present study investigated a potential structure-activity relationship between PFAS and hepatotoxicity. As such, the effects of thirteen PFAS with varying carbon chain-length and functional head-groups (in a concentration range of 0-800µM) on the cell viability of HepG2 cells and intracellular reactive oxygen species formation have been tested using the MTT and DCFH assay, respectively. The exposure times were either 3 or 24h. In addition, intracellular PFAS levels were determined in HepG2 after 24h exposure. The present study demonstrated that the cytotoxicity of PFAS is dependent on their chain-length as cell viability decreased with increasing chain-length at both exposure times. Calculated Relative Potency Factors (RPF), based on the TC50 values, were used for a tentative ranking of PFAS regarding their hepatotoxicity: PFNA ˃ PFDA ˃ PFOS ≥ PFOA ˃ PFHxS ˃ PFBS ˃˃ PFHpA = PFHxA = PFBA = PFPrA = 6:2 FTOH = 4:2 = FTOH = 3:1 FTOH. Similar results were observed regarding intracellular reactive oxygen species generation at both exposure times, with a tentative ranking of: PFNA ˃ PFOS ˃ PFOA ≥ PFDA ˃ PFHxS ˃ PFBS ˃ PFBA ˃ PFHpA ≥ PFHxA ˃ PFPrA ˃ 6:2 FTOH = 4:2 FTOH = 3:1 FTOH. Moreover, a concentration-dependent reactive oxygen species generation has been observed for all PFSAs and PFCAs, but not for the FTOHs. In conclusion, the carbon chain-length and functional head-group of a PFAS determine their in vitro toxicity for the two toxicological endpoints assessed in the present study. Moreover, no effects were observed for the tested FTOHs. As such, the present study established a potential structure-activity relationship that opens the possibility of developing a predictive model to help with the risk assessment of PFAS in the future.

Placenta contains 3β-hydroxysteroid dehydrogenase/steroid Δ

Pyrimethamine (PYR) is used to treat parasitic infections including toxoplasmosis, pneumonia and cystoisosporiasis in HIV patients. Various oral medicines have shown phototoxicity therefore, we aimed to study the phototoxicity of PYR and its molecular mechanism involving stress responsive lysosomal protein Lamp2 and mitochondrial mediated signaling pathway under normal UVA/B exposure. We found that photodegradation and subsequent photoproduct formation was evident through LCMS/MS analysis. Photosensitized PYR produces ROS that cause damage to DNA, cell membrane and membrane bound organelles in human keratinocytes. PYR triggered cytotoxicity and phototoxicity that was evident through MTT and NRU assay respectively. Intracellular ROS generation caused phosphatidyl serine (PS) translocation in cell membrane, lysosome membrane permeabilization (LMP) and mitochondrial membrane potential (MMP) collapse that was further validated through caspase3 activation. DNA damage was measured as tail DNA formation and cell cycle arrest in G1 phase. Photosensitized PYR induces oxidative stress in the form of overexpression of Lamp2 that ultimately led to cellular apoptosis. Moreover, the effects of UVB were higher than UVA, probably due to its direct interaction with various macromolecules. We propose that photoexcited PYR may be harmful to human health even at normal sunlight exposure. Therefore, protective procedures should be practiced during PYR medication.

Cyanobacterial blooms, usually dominated by Microcystis aeruginosa, pose a serious threat to global freshwater ecosystems owing to their production and release of various harmful secondary metabolites. Detection of the chemicals in M. aeruginosa exudates using metabolomics technology revealed that phytosphingosine (PHS) was one of the most abundant compounds. However, its specific toxicological mechanism remained unclear. CNE-2 cells were selected to illustrate the cytotoxic mechanism of PHS, and it was determined to cause excessive production of reactive oxygen species and subsequently damage the mitochondrial structure. Mitochondrial membrane rupture led to matrix mitochondrial membrane potential disintegration, which induced Ca

Humans are exposed to cadmium via a variety of anthropogenic and natural pathways. Hypoxia, a key pathophysiological consequence of chronic obstructive pulmonary disease (COPD), as well as anemia, induce expression of many genes, including divalent metal transporter (DMT-1) , to induce cell adaptation to decreased pO

Circular RNAs (circRNAs) are emerging as novel regulators in the biological development of various diseases, but their expression profiles, functions and mechanisms in silicosis and pulmonary fibrosis remain largely unexplored. In this study, we constructed a mouse model of pulmonary fibrosis by intratracheal injection of silica particles and then performed transcriptome RNA sequencing of lung tissues. The results showed that 78 circRNAs, 39 miRNAs and 262 mRNAs were differentially expressed. Among them, five circRNAs, three miRNAs and four mRNAs were further selected, and their abnormal expression was verified in mouse fibrotic lung tissues by RT-qPCR assay. The circRNA-associated ceRNA network including 206 ceRNA triplets was constructed based on abnormally expressed circRNAs, miRNAs and mRNAs, and miR-199b-5p, miR-296-5p and miR-708-5p were identified as hub miRNAs connected to circRNAs and mRNAs. Subsequently, GO and KEGG pathway enrichment analyses were performed to detect the potential roles of differentially expressed mRNAs in pulmonary fibrosis, which were mainly involved in immune response, Th17 cell differentiation, NF-κB signaling pathway and PI3K-Akt signaling pathway. Furthermore, we identified that hsa_circ_0006916 was up-regulated in pulmonary fibrosis. To characterize the potential role of hsa_circ_0006916, we transfected siRNA targeting hsa_circ_0006916 into alveolar macrophages and found that knockdown of hsa_circ_0006916 significantly increased the expression levels of M1 molecules IL-1β and TNF-α and reduced the expression level of M2 molecule TGF-β1, indicating that hsa_circ_0006916 may play an important role in the activation of M1-M2 polarization effect in macrophages. Our results provided important evidence on the possible contribution of these abnormal circRNAs to the development of silicosis and pulmonary fibrosis.

The random forest (RF) algorithm, together with ten Dragon descriptors, was used to develop a quantitative structure-toxicity/activity relationship (QSTR/QSAR) model for a larger data set of 1792 chemical toxicity pIGC