Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models.

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

Combined association of urinary volatile organic compounds with chronic bronchitis and emphysema among adults in NHANES 2011-2014: The mediating role of inflammation.

Evidence on the association of volatile organic compounds (VOCs) with chronic bronchitis (CB) and emphysema is spare and defective. To evaluate the relationship between urinary metabolites of VOCs (mVOCs) with CB and emphysema, and to identify the potential mVOC of paramount importance, data from NHANES 2011-2014 waves were utilized. Logistic regression was conducted to estimate the independent association of mVOCs with respiratory outcomes. Least absolute shrinkage and selection operator (LASSO) regression was performed to screen a parsimonious set of CB- and emphysema-relevant mVOCs that were used for further co-exposure analyses of weight quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR). Mediation analysis was employed to detect the mediating role of inflammatory makers in such associations. In single exposure analytic model, nine mVOCs were individually and positively associated with CB, while four mVOCs were with emphysema. In WQS regression, positive association between LASSO selected mVOCs and CB was identified (OR = 1.82, 95% CI: 1.25 to 2.69), and N-acetyl-S-(4-hydroxy-2-butenyl)-l-cysteine (MHBMA3) weighted the highest. Results from BKMR further validated such combined association and the significance of MHBMA3. As for emphysema, significantly positive overall trend of mVOCs was only observed in BKMR model and N-acetyl-S-(N-methylcarbamoyl)-l-cysteine (AMCC) contributed most to the mixed effect. White blood cell count (WBC) and lymphocyte number (LYM) were mediators in the positive pattern of mVOCs mixture with CB, while association between mVOCs mixture and emphysema was significantly mediated by LYM and segmented neutrophils num (NEO). This study demonstrated that exposure to VOCs was associated with CB and emphysema independently and combinedly, which might be partly speculated that VOCs were linked to activated inflammations. Our findings shed novel light on VOCs related respiratory illness, and provide a new basis for the contribution of certain VOCs to the risk of CB and emphysema, which has potential public health implications.

Evaluation of Kidney Injury Using Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI: An Experimental Study in Rats With Carbon Tetrachloride-Induced Liver Cirrhosis.

BACKGROUND: Serum creatinine (Scr) may be not suited to timely and accurately reflect kidney injury related to chronic liver disease. Currently, the ability of arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) sequences to evaluate renal blood flow (RBF) and blood oxygen in chronic liver disease remains to be verified. PURPOSE: To investigate the value of ASL and BOLD imaging in evaluating hemodynamics and oxygenation changes during kidney injury in an animal model of chronic liver disease. STUDY TYPE: Prospective. ANIMAL MODEL: Chronic liver disease model was established by subcutaneous injection of carbon tetrachloride. Forty-three male Sprague-Dawley rats (8 weeks) were divided into a pathological group (0, 2, 4, 6, 8, 12 weeks, each group: N = 6) and a continuous-scanning group (N = 7). FIELD STRENGTH/SEQUENCE: 3-T, ASL, BOLD, and T2W. ASSESSMENT: Regions of interest in the cortex (CO), outer stripe of the outer medulla (OSOM), and inner stripe of the outer medulla (ISOM) are manually delineated. The RBF and T2* values at each time point (0, 2, 4, 6, 8, 12 weeks) are measured and compared. Hematoxylin-eosin score (HE Score, damage area scoring method), alpha-smooth muscle actin (α-SMA), hypoxia-inducible factor-1alpha (HIF-1α), peritubular capillar (PTC) density, Scr, and neutrophil gelatinase-associated lipocalin were harvested. STATISTICAL TESTS: Analysis of variance, Spearman correlation analysis, Kruskal-Wallis tests, and receiver operating characteristic analysis with the area under the curve (AUC). A P-value <0.05 was considered statistically significant. RESULTS: Renal RBF and T2* values of CO, OSOM, and ISOM were significantly different from baseline. Both RBF and T2* were significantly correlated with HE Score, α-SMA, HIF-1α, and PTC density (|r| = 0.406-0.853). RBF demonstrated superior diagnostic capability in identifying severe kidney injury in this model of chronic liver disease (AUC = 0.964). DATA CONCLUSION: Imaging by ASL and BOLD may detect renal hemodynamics and oxygenation changes related to chronic liver disease early. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 2.

Association Between Urinary Glyphosate Exposure and Cognitive Impairment in Older Adults from NHANES 2013-2014.

BACKGROUND: Glyphosate is the most commonly used herbicide with potential neurotoxicity. However, limited epidemical evidence is found in the relationship between glyphosate and cognitive impairment, especially in the cognitive-disrupting sensitive elderly populations. OBJECTIVE: This study aimed to examine the association of urinary glyphosate exposure with cognitive impairment in the United State (US) older adults. METHODS: Cognitive impairment was determined by the following four tests: the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Immediate Recall test (IR), the CERAD Delayed Recall tests (DR), the Animal Fluency (AF) test and the Digit Substitution test (DSST). Survey weighted logistic regression and restricted cubic splines were applied to evaluate and visualize the association between glyphosate and cognitive impairment. RESULTS: A total of 465 elderly adults were identified in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle, and among them, 83.87% individuals had detectable urinary levels of glyphosate (0.628 ng/mL in average). After adjusting for the potential covariates, glyphosate was significantly linked to increased DR and AF impairment, and the corresponding ORs were 1.52 (1.01 to 2.30, p = 0.049) and 1.69 (1.11 to 2.59, p = 0.019), respectively. No significant association was identified between glyphosate and IR or DSST impairment. The RCS plot further confirmed the linear and positive relationships between glyphosate and DR and AF impairment. CONCLUSIONS: These findings suggested that exposure to glyphosate might be associated with declined cognitive function in the elderly, and it might be prudent to evaluate cognitive outcomes for aged individuals with glyphosate exposures.

Endothelium-Mimetic Surface Modification Improves Antithrombogenicity and Enhances Patency of Vascular Grafts in Rats and Pigs.

We first identified thrombomodulin (TM) and endothelial nitric oxide (NO) synthase as key factors for the antithrombogenic function of the endothelium in human atherosclerotic carotid arteries. Then, recombinant TM and an engineered galactosidase responsible for the conversion of an exogenous NO prodrug were immobilized on the surface of the vascular grafts. Surface modification by TM and NO cooperatively enhanced the antithrombogenicity and patency of vascular grafts. Importantly, we found that the combination of TM and NO also promoted endothelialization, whereas it reduced adverse intimal hyperplasia, which is critical for the maintenance of vascular homeostasis, as confirmed in rat and pig models.

Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice.

Phthalates are a group of neurotoxicants with cognitive-disrupting potentials. Given the structural diversity of phthalates, the corresponding neurotoxicity is dramatically altered. To identify the potential contributions of different phthalates on the process of cognitive impairment, data of 836 elders from the NHANES 2011-2014 cycles were used. Survey-weighted logistic regression and principal component analysis-weighted quantile sum regression (PCA-WQSR) models were applied to estimate the independent and combined associations of 11 urinary phthalate metabolites with cognitive deficit (assessed by 4 tests: Immediate Recall (IR), Delayed Recall (DR), Animal Fluency (AF), and Digit Symbol Substitution Test (DSST)) and to identify the potential phthalate with high weight. Laboratory mice were further used to examine the effect of phthalates on cognitive function and to explore the potential mechanisms. In logistic regression models, MBzP was the only metabolite positively correlated with four tests, with ORs of 2.53 (quartile 3 (Q3)), 2.26 (Q3), 2.89 (Q4) and 2.45 (Q2), 2.82 (Q4) for IR, DR, AF, and DSST respectively. In PCA-WQSR co-exposure models, low-molecular-weight (LMW) phthalates were the only PC positively linked to DSST deficit (OR: 1.93), which was further validated in WQSR analysis (WQS OR7-phthalates: 1.56 and WQS OR8-phthalates: 1.55); consistent with the results of logistic regression, MBzP was the dominant phthalate. In mice, butyl benzyl phthalate (BBP), the parent phthalate of MBzP, dose-dependently reduced cognitive function and disrupted hippocampal neurons. Additionally, the hippocampal transcriptome analysis identified 431 differential expression genes, among which most were involved in inhibiting the neuroactive ligand-receptor interaction pathway and activating the cytokine-cytokine receptor interaction pathway. Our study indicates the critical role of BBP in the association of phthalates and cognitive deficits among elderly individuals, which might be speculated that BBP could disrupt hippocampal neurons, activate neuroinflammation, and inhibit neuroactive receptors. Our findings provide new insight into the cognitive-disrupting potential of BBP.

Adolescence is a sensitive period for acrylamide-induced sex hormone disruption: Evidence from NHANES populations and experimental mice.

Acrylamide (AA) is widely contaminated in environment and diet. However, the association of AA and sex hormones has rarely been investigated, especially in adolescents, a period of particular susceptibility to sex hormone disruption. In this study, survey-weighted multivariate linear regression models were conducted to determine the association between AA Hb biomarkers [HbAA and glycidamide (HbGA)] and sex hormones [total testosterone (TT) and estradiol (E2)] in a total of 3268 subjects from National Health and Nutrition Examination Survey (NHANES) 2013-2016 waves. Additionally, adult and pubertal mice were treated with AA to assess the effect of AA on sex hormones and to explore the potential mechanisms. Among all the subjects, significant negative patterns for HbGA and sex hormones were identified only in youths (6-19 years old), with the lowest ß being - 0.53 (95% CI: -0.80 to -0.26) for TT in males and - 0.58 (95% CI: -0.93 to -0.23) for E2 in females. Stratified analysis further revealed significant negative associations between HbGA and sex hormones in adolescents, with the lowest ß being - 0.58 (95% CI: -1.02 to -0.14) for TT in males and - 0.54 (95% CI: -1.03 to -0.04) for E2 in females, while there were no significant differences between children or late adolescents. In mice, the levels of TT and E2 were dramatically reduced in AA-treated pubertal mice but not in adult mice. AA disturbed the expression of genes in the hypothalamic-pituitary-gonadal (HPG) axis, induced apoptosis of hypothalamus-produced gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus and reduced serum and hypothalamic GnRH levels in pubertal mice. Our study indicates AA could reduce TT and E2 levels by injuring GnRH neurons and disrupting the HPG axis in puberty, which manifested as severe endocrine disruption on adolescents. Our findings reinforce the idea that adolescence is a vulnerable stage in AA-induced sex hormone disruption.

Multi-parametric magnetic resonance imaging of liver regeneration in a standardized partial hepatectomy rat model.

BACKGROUND: We aimed to evaluate the correlation between the pathological changes and multi-parameter MRI characteristics of liver regeneration (LR) in a standard partial hepatectomy (PH) rat model. METHODS: Seventy Sprague-Dawley rats were randomly divided into two groups: MR scan group (n = 14) and pathologic analysis (PA) group (n = 56). All 14 rats in the MR group underwent liver T1 mapping, T2 mapping, and diffusion kurtosis imaging before and the 1st, 2nd, 3rd, 5th, 7th, 14th, and 21st day after 70% hepatectomy. Seven rats in the PA group were euthanized at each time point to determine Ki-67 indices, hepatocyte size (HTS), steatosis grade, and inflammation score. RESULTS: Liver T1 and T2 values increased to maximum on day 2 (P < 0.001 vs. baseline), D and K values decreased to minimum on day 3 and 2, respectively (P < 0.001 vs. baseline), then all parameters returned to baseline gradually. Hepatocyte Ki-67, hepatocyte size, steatosis grade, and inflammation score initially increased after surgery (P < 0.05 vs. baseline), followed by a gradual decline over time. Both T2 and K values correlated well with Ki-67 indices (r = 0.765 and - 0.807, respectively; both P < 0.001), inflammation (r = 0.809 and - 0.724, respectively; both P < 0.001), steatosis grade (r = 0.814 and - 0.725, respectively; both P < 0.001), and HTS (r = 0.830 and - 0.615, respectively; both P < 0.001). CONCLUSIONS: PH induced liver changes that can be observed on MRI. The MRI parameters correlate with the LR activity and allow monitoring of LR process.

Screw analysis and experimental study of spatial noncircular gear compound transmission.

Curve face gear pair and noncircular bevel gear pair are collectively referred to as spatial noncircular gear pair (SNCGP). Different from the traditional gear transmission with fixed shafts, spatial noncircular gear (SNCG) compound transmission can realize compound motion with variable transmission ratio between intersecting axes, and has a broad engineering application prospect. It includes two categories named speed reduction and speed increase. Based on the gear meshing theory, screw theory and calculus, a screw analysis method of SNCG compound transmission was proposed, which directly and comprehensively reflected the compound motion characteristics of rotation and axial movement. Firstly, a unified coordinate system was established. The screw geometric characteristics of compound motion were discussed, including instant screw axis, axode, pitch surface and its normal equidistant surface. The screw principle of compound motion was revealed. Then, according to this method, combined with the motion process of generator with different tooth profiles, the tooth surface of each SNCG was obtained. Finally, gear machining, tooth surface measurement, transmission ratio measurement and axial displacement measurement were carried out, which verified the correctness of this screw analysis method for SNCG compound transmission, and laid a foundation for further study and application.

Series of Intravoxel Incoherent Motion and T2* Magnetic Resonance Imaging Mapping in Detection of Liver Perfusion Changes and Regeneration Among Partial Hepatectomy in Sprague-Dawley Rats.

RATIONALE AND OBJECTIVES: To evaluate liver perfusion changes and their effect on liver regeneration (LR) after partial hepatectomy (PH) using intravoxel incoherent motion (IVIM) and T2* mapping in a rat model. METHODS: One hundred and two rats underwent 30%, 50%, or 70% PH. Within each group (n = 34), rats in MR imaging subgroup (n = 10) underwent liver IVIM and T2* mapping before and within 2 h, 1, 2, 3, 5, 7, 14, and 21 days post-PH to measure D*, perfusion fraction (PF), and T2* values. Three rats from histologic subgroup (n = 24) sacrificed at each time point for hepatocyte Ki-67 indices and diameters measurement. RESULTS: Liver D* and PF values decreased immediately post-PH, then returned to original level as LR progressed in all groups. PF values in 70% PH group were significantly lower than in the other two groups (p < .05). D* and PF values correlated significantly with hepatocyte Ki-67 indices (r = -0.588 to -0.915; p < .05) and hepatocyte diameter (r = -0.555 to -0.792; p < .05). Liver T2* values decreased immediately within 2 h post-PH, then increased to a high level and followed with returning to original level gradually. The duration of the high T2* levels was consistent with Ki-67 indices. CONCLUSIONS: Liver perfusion decreased immediately followed with increasing gradually after PH. IVIM and T2* mapping are promising methods for monitoring changes of liver perfusion. IVIM-derived D* value is the best indicator in reflecting the process of LR noninvasively.

Assessment of Fibrotic Liver Regeneration After Partial Hepatectomy With Intravoxel Incoherent Motion Diffusion-Weighted Imaging: An Experimental Study in a Rat Model With Carbon Tetrachloride Induced Liver Injury.

PURPOSE: To determine whether intravoxel incoherent motion (IVIM) parameters correlate with liver regeneration and function recovery after partial hepatectomy (PH) in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Sixty-two adult Sprague-Dawley rats were divided into the control group and the fibrosis group with CCl4 injection for 8 weeks. At the end of the 8th week, all rats received left lateral lobe liver resection. Within each group, IVIM imaging (n = 10/group) and histologic and biochemical analyses (n = 3/group/time point) were performed pre- and post-PH (on days 1, 2, 3, 5, 7, 14, and 21). Differences in liver IVIM parameters and correlation between IVIM parameters and Ki-67 indices, hepatocyte diameter, alanine transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) values were analyzed. RESULTS: Post-PH, liver true diffusion coefficient (D) values decreased and pseudodiffusion coefficient (D*) and perfusion fraction (PF) values increased, then recovered to pre-PH levels gradually in both fibrosis and control rats. PF in fibrosis group were significantly higher than in controls from 3 to 21 days (P < 0.05). In fibrosis rats, both Ki-67 indices and hepatocyte diameters increased, and a strong correlation was found between PF and Ki-67 indices (r = -0.756; P = 0.03), D* and PF values and ALT, AST, and TBil values (r = -0.762 to -0.905; P < 0.05). In control rats, only hepatocyte diameters increased, and all IVIM parameters correlated well with hepatocyte diameters, ALT, AST and TBil values (r = 0.810 to -1.000; P < 0.05). CONCLUSION: The regeneration pattern in fibrotic liver tissue was different compared with control livers. IVIM parameters can monitor liver regeneration and functional recovery non-invasively after PH.

Perfusion Analysis of Kidney Injury in Rats With Cirrhosis Induced by Common Bile Duct Ligation Using Arterial Spin Labeling MRI.

BACKGROUND: Arterial spin labeling (ASL) has been proven to be effective in ischemia-induced acute kidney injury (AKI); however, validation of ASL magnetic resonance imaging (MRI) is limited in AKI in the presence of cirrhosis. PURPOSE: To investigate the feasibility of ASL in revealing renal blood flow (RBF) changes in kidney injury in the presence of cirrhosis and to assess its value in the early diagnosis of disease. STUDY TYPE: Longitudinal. ANIMAL MODEL: Rats were randomized into baseline group (N = 3), sham surgery group (N = 18), and common bile duct ligation (BDL) group (N = 48). All groups were divided into six subgroups based on different sacrificed time points. FIELD STRENGTH/SEQUENCE: 3 T scanner, prototypic pulsed ASL sequence using flow-sensitive alternating inversion recovery preparation, half-Fourier acquisition single-shot turbo spin echo sequence. ASSESSMENT: RBF measurement was performed by ASL. Hematoxylin-eosin (HE) score, Hypoxia-inducible factor-1alpha (HIF-1α) score, peritubular capillar (PTC) density, alanine aminotransferase, aspartate aminotransferase, serum total bilirubin, total bile acids, serum creatinine (Scr), and blood urea nitrogen (BUN) were harvested. STATISTICAL TESTS: Analysis of variance, Pearson's correlation coefficient, and receiver operating characteristic curves were performed. P < 0.05 was considered statistically significant. RESULTS: RBF, HE score, HIF-1α score, and PTC density after BDL were significantly different from baseline. RBF was highly correlated with HE score, HIF-1α score, and PTC density (r = -0.7598, r = -0.7434, r = 0.6406, respectively). RBF and Scr began to differ significantly from baseline at day 3 and 7 after intervention, respectively. The areas under the curves of RBF, Scr, and BUN for distinguishing non-AKI from AKI in cirrhosis were 1.00, 0.888, and 0.911, while those for distinguishing mild from severe kidney injury were 0.961, 0.830, and 0.857, respectively. DATA CONCLUSION: ASL allows the longitudinal assessment of the degree of AKI induced by cholestatic cirrhosis in rats and can serve as a noninvasive marker for the early and accurate diagnosis of AKI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Bioaccumulation of BDE47 in testes by TiO2 nanoparticles aggravates the reproductive impairment of male zebrafish by disrupting intercellular junctions.

This study attempts to explore the potential impact of titanium dioxide nanoparticles (n-TiO2) on bioconcentration and reproductive impairments of male zebrafish in the presence of 2,2',4,4'-tetrabromodiphenyl ether (BDE47), the congener of PBDEs predominant in environment and most abundant in biosamples. n-TiO2 nanoparticles strongly adsorbed BDE47 to form BDE47/TiO2 complex, which was taken up into the testes of zebrafish, and increased the tissue burdens of both BDE47 and n-TiO2. Correspondingly, no observed toxic dose of n-TiO2 (100 µg/L) was found to aggravate the abnormal histological morphology of the testes and the decrease in egg production, gonadosomatic index, sexual hormone levels and related gene expression in zebrafish in the presence of BDE47 at 5 or 50 µg/L. In addition, n-TiO2 exacerbated the destruction resulting from the ultrastructural disassembly of intercellular connectivity of germ cells in zebrafish and the decrease in transepithelial electrical resistance in TM4 cells induced by BDE47. Furthermore, n-TiO2 enhanced BDE47 to initially activate p-JNK MAPK signaling pathway and subsequently triggered the downregulation of junction proteins (i.e., ZO-1, Connexin-43 and N-cadherin), leading to impaired cell-cell junctions in vivo and in vitro. Our results demonstrated that n-TiO2 should act as a carrier to facilitate the accumulation of BDE47 in zebrafish testes and result in a synergistic effect on BDE47-induced adverse reproductive outcomes via disruption of intercellular connectivity of zebrafish testes. This study is beneficial in providing a scientific basis for improving the health risk assessment of environmental pollutants, particularly those that coexist with nanoparticle contamination in realistic environments.

Rno-miR-224-5p contributes to 2,2',4,4'-tetrabromodiphenyl ether-induced low triiodothyronine in rats by targeting deiodinases.

Hypothyroidism is commonly associated with substantial adverse impacts on human health, and polybrominated diphenyl ether (PBDE), a kind of classic thyroid hormone disruptor, was speculated to be a potential environmental factor, but its effect on thyroxine metabolism has received little attention. In the present study, we investigated the role and mechanism of rno-miR-224-5p in deiodinase-mediated thyroxine metabolism in rats treated with 2,2',4,4'-tetrabromodiphenyl ether (BDE47), a predominant PBDE congener in humans. BDE47 decreased plasma triiodothyronine (T3) and thyroxine (T4) and increased reverse T3 (rT3) in the rats, and the expression of type 1 deiodinase (DIO1) and type 3 deiodinase (DIO3) increased in both the rats and H4-II-E cells. Rno-miR-224-5p was predicted to target dio1 instead of dio3, according to the TargetScan, miRmap.org and microRNA.org databases. Experiments showed that the rno-miR-224-5p level was decreased by BDE47 in a dose-dependent manner and confirmed that rno-miR-224-5p downregulated both DIO1 and DIO3 in the H4-II-E cells and in the rats, as determined using mimics and an inhibitor of rno-miR-224-5p. Furthermore, DIO1 was observed to be a direct functional target of rno-miR-224-5p, whereas DIO3 was indirectly regulated by rno-miR-224-5p via the phosphorylation of the MAPK/ERK (but not p38 or JNK) pathway. Reportedly, DIO1 and DIO3 act principally as inner-ring deiodinases and are responsible for the conversion of T4 to rT3, but not to T3, and the final clearance of thyroxine (mainly in the form of T2). Our results demonstrated that BDE47 induced low levels of T3 conversion through DIO1 and DIO3, which were regulated by rno-miR-224-5p. The findings suggest a novel additional mechanism of PBDE-induced thyroxine metabolism disorder that differs from that of PBDEs as environmental thyroid disruptors.

Perfluorooctane sulfonate disrupts the blood brain barrier through the crosstalk between endothelial cells and astrocytes in mice.

Perfluorooctane sulfonate (PFOS), a classic environmental pollutant, is reported to accumulate in brain and induce neurotoxicity. However, little is known the route and mechanism of its entrance in brain. In the present study, ICR mice were treated with PFOS for 28 days, the cerebral PFOS were measured and the morphological and ultrastructural changes of blood-brain barrier (BBB) were observed. Also, the expression and localization of the proteins related to the cerebral damages, tight junctions (TJs) and p38 activation were detected. Additionally, U87 cells were used to explore the role of p38 in PFOS-induced damages of astrocytes. PFOS significantly decreased the expression of TJ-related proteins (ZO-1, Claudin-5, Claudin-11, Occludin) in endothelial cells and disrupted BBB, which subsequently led PFOS to astrocytes and increased the expression of the proteins related to astrocytic damages (Aquaporin 4 and S100ß). These results aggravated BBB disruption and further increased the cerebral PFOS levels. Besides, phosphorylated p38 activation was involved into PFOS-induced astrocytic damages in vivo and in vitro. In conclusion, the crosstalk between endothelial cells and astrocytes facilitated the BBB disruption and increased the accumulation of PFOS in brain. Our findings provided a new insight into the toxicological and physiological profiles of PFOS-induced neurotoxicity.

Fenvalerate triggers Parkinson-like symptom during zebrafish development through initiation of autophagy and p38 MAPK/mTOR signaling pathway.

Fenvalerate (FEN), one of the most used synthetic pyrethroids, has the potential to interfere with human neural function. However, far too little attention was paid to the mechanism of FEN-induced neurotoxicity. Thus we exposed zebrafish to FEN from 4 to 120 h post fertilization (hpf), and analyzed the morphology and behavior of zebrafish. Our results showed that FEN decreased the survival rate of zebrafish, with increased malformation rates and abnormal behaviors. Furthermore, we found typical parkinson-like symptoms in FEN-exposed zebrafish with increases in parkinson's disease (PD), ubiquitin, and Lewy bodies-relevant genes. We also observed the loss of dopaminergic neurons in both FEN-exposed zebrafish and PC12 cells, which were all associated with PD-like symptoms. Besides, FEN activated autophagy by the enhanced expressions of p-mTOR, and LC3-II but the reduction of p62. Further, FEN initially activated p-p38 MAPK followed by p-mTOR, which triggered the transcription of genes responsible for autophagy process and prompted the Lewy bodies neuron generation leading to the PD-like symptoms. This process was inhibited by both 3-methyladenine (3-MA, an autophagy inhibitor) and SB203580 (a p38 MAPK selective inhibitor) in zebrafish and PC12 cells. These results suggest that FEN might cause parkinson-like symptom during zebrafish development through induction of autophagy and activation of p38 MAPK/mTOR signaling pathway. The study revealed the potential mechanism of FEN-induced neurotoxicity and should give new insights into a significant environmental risk factor of developing parkinson's disease.

Isoliquiritigenin as an antioxidant phytochemical ameliorates the developmental anomalies of zebrafish induced by 2,2',4,4'-tetrabromodiphenyl ether.

2,2',4,4'-Tetrabromodiphenyl ether (BDE47) is the most abundant PBDE congeners in biological samples. It has strong tendencies to bioaccumulate and potentially endangers development of mammals through oxidative stress. Isoliquiritigenin (ISL), an emerging natural chalcone-type flavonoid, possesses various biological and pharmacological properties, including antioxidant, anti-allergic, anti-inflammatory, anti-tumor and estrogenic activities. The purpose of the study is to explore the antioxidant effect of ISL on the amelioration of developmental anomalies induced by BDE47. Zebrafish (Danio rerio) embryos were exposed to BDE47 (1 and 10 µM) and/or ISL (4 µM) for 4 to 120 hours post fertilization (hpf), and the morphology, development, behavior, oxidative stress status and related genes expression were assessed. The results showed that BDE47 contributed to dose-dependent growth retardation and deformities, including delayed hatching, spinal curvature, reduced body length, increased death rate, aberrant behaviors and impaired dark-adapted vision, which were significantly mitigated by ISL. Besides, ISL ameliorated excessive ROS accumulation, and exaggerated the expressions of apoptosis-related genes p53, Bcl-2, caspase 3 and caspase 9 induced by BDE47, suggesting that ISL protected zebrafish from the developmental toxicity of BDE47 by inactivation of programmed apoptosis and activation of antioxidant signaling pathways. Taken together, developing ISL as a dietary supplement might be a promising preventive strategy for the amelioration of developmental toxicity induced by environmental pollutants.