Design and bio-evaluation of novel millepachine derivatives targeting tubulin colchicine binding site for treatment of osteosarcoma.

Microtubules are recognized as an appealing target for cancer treatment. We designed and synthesized of novel tubulin colchicine binding site inhibitors based on millepachine. Biological evaluation revealed compound 5h exhibited significant antiproliferative activity against osteosarcoma cell U2OS and MG-63. And compound 5h also remarkably inhibited tubulin polymerization. Further investigations indicated compound 5h not only arrest U2OS cells cycle at the G2/M phases, but also induced U2OS cells apoptosis in dose-dependent manners. Moreover, compound 5h was verified to inhibit cell migration and angiogenesis of HUVECs, induce mitochondrial membrane potential decreased and promoted the elevation of ROS levels. Furthermore, compound 5h exhibited remarkable effects on tumor growth in vivo, and the TGI rate was up to 84.94 % at a dose of 20 mg/kg without obvious toxicity. These results indicated that 5h may be an appealing tubulin inhibitor for treatment of osteosarcoma.

The Role of Copper-Induced M2 Macrophage Polarization in Protecting Cartilage Matrix in Osteoarthritis.

BACKGROUND The pathological mechanism of osteoarthritis is still unclear. The regulation of the immune microenvironment has been of growing interest in the progression and treatment of osteoarthritis. Macrophages with different phenotypes, producing different cytokines, have been linked to the mechanism of cartilage injury in osteoarthritis. Copper ions play a role in the immune response and are involved in the pathological mechanisms of osteoarthritis by affecting the metabolism of the cartilage matrix. Bioactive glass (BG) is an osteogenic material with superior biocompatibility. Here, we report on the regulatory behavior of macrophages using a copper-based composite BG material. MATERIAL AND METHODS Cu-BGC powder was prepared by sol-gel method, and scaffolds were fabricated and characterized using 3D printing. Macrophage cultures grown with Cu-BGC were examined for cell culture and proliferation. The effect of Cu-BGC on the degradation metabolism of chondrocytes, cultured in the environment of inflammatory cytokine IL-1ß, was determined. In addition, the morphology of macrophages, secretion of inflammatory cytokines, and expression of surface markers were examined. RESULTS The results show that Cu-BGC promotes macrophage proliferation at a range of concentrations and increases the secretion of anti-inflammatory cytokines while inhibiting proinflammatory cytokines. At the same time, M2-type cell surface markers are definitely expressed and the morphology of macrophages is altered. In addition, Cu-BGC inhibited the degradation metabolism of chondrocytes in the inflammatory environment induced by IL-1ß. CONCLUSIONS These results suggest that Cu-BGC induced macrophage polarization into an M2 type anti-inflammatory phenotype, and inhibition of immune injury response may play a role in delaying cartilage matrix damage in osteoarthritis.

Marked gut microbiota dysbiosis and increased imidazole propionate are associated with a NASH Göttingen Minipig model.

BACKGROUND: Gut microbiota dysbiosis is associated with the development of non-alcoholic steatohepatitis (NASH) through modulation of gut barrier, inflammation, lipid metabolism, bile acid signaling and short-chain fatty acid production. The aim of this study was to describe the impact of a choline-deficient amino acid defined high fat diet (CDAHFD) on the gut microbiota in a male Göttingen Minipig model and on selected pathways implicated in the development of NASH. RESULTS: Eight weeks of CDAHFD resulted in a significantly altered colon microbiota mainly driven by the bacterial families Lachnospiraceae and Enterobacteriaceae, being decreased and increased in relative abundance, respectively. Metabolomics analysis revealed that CDAHFD decreased colon content of short-chain fatty acid and increased colonic pH. In addition, serum levels of the microbially produced metabolite imidazole propionate were significantly elevated as a consequence of CDAHFD feeding. Hepatic gene expression analysis showed upregulation of mechanistic target of rapamycin (mTOR) and Ras Homolog, MTORC1 binding in addition to downregulation of insulin receptor substrate 1, insulin receptor substrate 2 and the glucagon receptor in CDAHFD fed minipigs. Further, the consequences of CDAHFD feeding were associated with increased levels of circulating cholesterol, bile acids, and glucagon but not total amino acids. CONCLUSIONS: Our results indicate imidazole propionate as a new potentially relevant factor in relation to NASH and discuss the possible implication of gut microbiota dysbiosis in the development of NASH. In addition, the study emphasizes the need for considering the gut microbiota and its products when developing translational animal models for NASH.

Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo.

Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid ß-oxidation is suppressed while the peroxisomal fatty acid ß -oxidation is increased. At higher doses, however, both ß -oxidation pathways are upregulated.

Atmospheric-pressure chemical ionization tandem mass spectrometry (APGC/MS/MS) an alternative to high-resolution mass spectrometry (HRGC/HRMS) for the determination of dioxins.

The use of a new atmospheric-pressure chemical ionization source for gas chromatography (APGC) coupled with a tandem quadrupole mass spectrometry (MS/MS) system, as an alternative to high-resolution mass spectrometry (HRMS), for the determination of PCDDs/PCDFs is described. The potential of using atmospheric-pressure chemical ionization (APCI) coupled to a tandem quadrupole analyzer has been validated for the identification and quantification of dioxins and furans in different complex matrices. The main advantage of using the APCI source is the soft ionization at atmospheric pressure, which results in very limited fragmentation. APCI mass spectra are dominated by the molecular ion cluster, in contrast with the high energy ionization process under electron ionization (EI). The use of the molecular ion as the precursor ion in MS/MS enhances selectivity and, consequently, sensitivity by increasing the signal-to-noise ratios (S/N). For standard solutions of 2,3,7,8-TCDD, injections of 10 fg in the splitless mode on 30- or 60-m-length, 0.25 mm inner diameter (id), and 25 µm film thickness low-polarity capillary columns (DB5MS type), signal-to-noise (S/N) ratios of >10:1 were routinely obtained. Linearity was achieved in the region (correlation coefficient of r(2) > 0.998) for calibration curves ranging from 100 fg/µL to 1000 pg/µL. The results from a wide variety of complex samples, including certified and standard reference materials and samples from several QA/QC studies, which were previously analyzed by EI HRGC/HRMS, were compared with the results from the APGC/MS/MS system. Results between instruments showed good agreement both in individual congeners and toxic equivalence factors (TEQs). The data show that the use of APGC in combination with MS/MS for the analysis of dioxins has the same potential, in terms of sensitivity and selectivity, as the traditional HRMS instrumentation used for this analysis. However, the APCI/MS/MS system, as a benchtop system, is much easier to use.

Levels and distribution of hexabromocyclododecane (HBCD) in environmental samples near manufacturing facilities in Laizhou Bay area, East China.

A total of 55 samples including soil, sediment, plants (cypress, reed and seepweed) and aquatic species were collected at locations around hexabromocyclododecane (HBCD) manufacturing facilities in Laizhou Bay area, East China. HBCD was determined at concentrations ranging between 0.88 and 6901 ng g(-1) dry weight (dw), 2.93-1029 ng g(-1) dw, 8.88-160241 ng g(-1) dw, and 7.09-815 ng g(-1) lipid weight (lw), respectively. Significant negative correlations (r(2) = 0.54, p = 0.006) were observed between HBCD concentrations in soils and the distance from the manufacturing facility, and the concentrations became constant when the distance was >4 km. The calculation results on the bioaccumulation factors (BAFs) suggested that HBCD may be accumulated in plants. Tissue-specific bioaccumulation of HBCD diastereoisomers was found in aquatic species. For example, in crabs the highest concentrations of HBCD (815 ng g(-1) lw for female and 446 ng g(-1) lw for male) were observed in the gill. Besides the gill, α-HBCD was more preferentially accumulated in the spermary and ovary, while ß- and γ-HBCD were more accumulated in the muscle. A similar distribution was also observed in roe and muscle of goby fish.

Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2, and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.

Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334). Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.

gp130/STAT3 signaling is required for homeostatic proliferation and anabolism in postnatal growth plate and articular chondrocytes.

Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a molecular circuit that regulates chondrogenic cell maintenance and output and reveals a pivotal positive function of IL-6 family cytokines in the skeletal system with direct implications for skeletal development and regeneration.

Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Conservative vs Surgical Treatment of Impacted Femoral Neck Fracture in Patients 75 Years and Older.

OBJECTIVE: To evaluate the safety and effectiveness of conservative treatment (CST), internal fixation (IF), and hemiarthroplasty (HA) in treating patients older than 75 years with impacted femoral neck fracture (IFNF). DESIGN: A randomized clinical trial to compare clinical outcomes of CST, IF, and HA in IFNF patients older than 75 years with a 1:1:1 ratio. SETTING: Nanjing First Hospital, Nanjing Medical University, Nanjing, China. PARTICIPANTS: A total of 154 patients with IFNF aged between 75 and 97 years. INTERVENTION: Patients with IFNF were allocated to CST, IF, and HA. They all received a 36-month follow-up. MEASUREMENTS: All patients were evaluated by Harris hip score (HHS) (primary outcome) for hip function, European Quality of Life-5 Dimensions (EQ-5D) index scores for health-related quality of life, and visual analogue scale score for hip pain. Operation duration, blood loss, mortality, union rate, complications, and reoperation were also recorded. Assessors were blind to the type of treatment. RESULTS: The baseline parameters of the three groups were similar. IF group had much lower blood loss than HA group (P < .05), while no significant difference in operative duration was found between the two groups (P > .05). HHS in HA group was significantly higher at 1, 3, and 6 months (P < .05), but no significant difference in HHS was found between CST and IF groups at any of the time points during the overall follow-up (P > .05). EQ-5D index score was higher in HA group at each follow-up within 1 year (P < .05), but the difference was not significant at 2- and 3-year follow-up (P > .05). There was no significant difference in mortality among the three groups at each follow-up point (P > .05). The nonunion rate was 11.76% (6/51) in CST group and 9.80% (5/51) in IF group and showed no significant difference (P > .05). CONCLUSION: CST may be a feasible way for IFNF in the older patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219943. J Am Geriatr Soc 68:2214-2221, 2020.

Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes.

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.

7,8-Dihydroxyflavone activates Nrf2/HO-1 signaling pathways and protects against osteoarthritis.

The aim of the present study was to investigate the effect of 7,8-dihydroxyflavone (7,8-DHF) against osteoarthritis (OA) and examine its regulatory role in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway in chondrocytes. Primary mouse chondrocytes were treated with 7,8-DHF to examine the expression of Nrf2 and downstream heme oxygenase 1 (HO-1). The surgical destabilization of the medial meniscus model was used to assess the effectiveness of 7,8-DHF in protecting the cartilage from damage, with knee cartilage harvested from mice for histological analysis. The results revealed that 7,8-DHF activated the Nrf2 signaling pathway in primary chondrocytes. Cartilage degradation in the 7,8-DHF-treated group was reduced significantly compared with that in the vehicle-treated group, according to histological evaluation. The gene expression of matrix metalloproteinase (MMP)1, MMP3, MMP13, interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α were reduced in the cartilage of OA mice following 7,8-DHF treatment. Genetic and protein analyses indicated that the expression levels of HO-1 were upregulated in the cartilage of the knee with OA, and 7,8-DHF treatment further promoted the induction of HO-1. These results suggest that 7,8-DHF may serve as a potential therapeutic agent in OA.

Clinical application of a new device for minimally invasive circumcision.

AIM: To study the clinical effects of a disposable circumcision device in treatment of male patients of different ages with either phimosis or excess foreskin. METHODS: One thousand two hundred patients between the age of 5 and 95 years underwent circumcision using this procedure in the 2-year period between October 2005 and September 2007. Of these cases, 904 had excess foreskin and 296 were cases of phimosis. RESULTS: In 96.33% of the cases the incision healed, leaving a minimal amount of the inner foreskin with no scarring and producing good cosmetic results. There were no incidents of device dislocation or damage to the frenulum. The average operative time was 2.5 min for excess foreskin, and 3.5 min for phimosis. During the 7 days of wearing the device, mild to moderate edema occurred in 10.08% of cases with excess foreskin and in 2.58% of those with phimosis. Edema in the frenulum was seen in 1.67% of patients, and only 0.67% had an infection of the incision. A total of 86.25% of patients reported pain due to penile erection. After removal of the device, 0.58% of the cases had minimal bleeding around the incision, and 2.42% had wound dehiscence. CONCLUSION: The new device can be applied to an overwhelming majority of patients with phimosis and excess foreskin. This technique is relatively simple to perform, and patients who underwent this surgery had very few complications. Antibiotics were not required and patients reported less pain than those who were circumcised using conventional methods. Circumcision with this device requires minimal tissue manipulation, and is quicker and safer than circumcision using conventional techniques.

Analysis of brominated flame retardants and their derivatives by atmospheric pressure chemical ionization using gas chromatography coupled to tandem quadrupole mass spectrometry.

A validated method using an atmospheric pressure chemical ionization source for coupling gas chromatography (GC-APCI) to tandem quadrupole mass spectrometry (MS/MS) for the determination of brominated flame retardants (BFRs) is presented. Polybrominated diphenyl ethers (PBDEs), their methoxylated derivatives (MeO-PBDEs) and other emerging BFRs were included in this study. The method showed good linearity and repeatability. The relative standard deviation (RSD) of the relative response factors (RRFs) of all compounds was below 16%. Repeatability for BFRs was tested on one or two concentration levels of calibration standards with RSDs for RRFs below 16%. The lowest calibration standards (0.075-0.1pg/µL for emerging BFRs, BDE 209 and MeO-PBDEs mixtures, 0.625-6.25pg/µL for Br1-9 PBDEs mixtures) were used as instrument detection limits (IDL). The method was applied on biotic samples, including fish, osprey, and seal. In general, BDE 209 and decabromodiphenyl ethane (DBDPE) were detected in 50% of the seal samples. A 100% detection rate was achieved for 6-MeO-BDE 47 in all the samples (72-580pg/g ww in osprey samples, 24,000-96,000pg/g ww in seal samples and 78-99pg/g ww in fish samples). All Br3-6 PBDEs (BDE 28, 47, 99, 100, 153, 154) were detected in all the samples (ranging from 12 to 20,000pg/g ww), while BDE 183 was detected in 60% of the osprey eggs, 20% of the seal samples and below MDL in all fish samples. The results presented indicate the capability of the GC-APCI-MS/MS system for the detection and quantification of BFRs.

MMC controlled-release membranes attenuate epidural scar formation in rat models after laminectomy.

Epidural scar formation after laminectomy impede surgical outcomes of decompression. Mitomycin C (MMC) has been demonstrated to have significant inhibitory effects on epidural scar. This study was undertaken to develop an effective MMC controlled­release membrane and to investigate its effects on epidural scar in rat models of laminectomy. A total of 72 rats that underwent laminectomy were divided into three groups. Among them, 24 were treated with mitomycin C­polylactic acid (MMC-PLA) controlled­release membrane, 24 with mitomycin C-polyethylene glycol (MMC-PEG) controlled-release membrane, and no treatment was performed for the remaining 24 rats (control group). In the following 4 weeks, magnetic resonance image (MRI), macroscopic observation, histology and hydroxyproline (Hyp) concentration analysis were performed to explore the effects of these three therapies on epidural scar. MRI revealed a significant reduction of epidural fibrosis in MMC-PLA and MMC-PEG treatment groups, compared with the control group. Histological results also showed that collagen deposition was significantly reduced after being treated with MMC-PLA or MMC-PEG membranes. Likewise, Hyp concentrations of the epidural scar tissue in MMC-PLA and MMC-PEG groups were markedly lower than those in the control group. However, regarding the effects on reducing epidural scar, no significant difference was found between the MMC-PLA and MMC-PEG groups. In conclusion, MMC-PLA and MMC-PEG membranes are safe and effective in reducing fibrosis. Thus, MMC-controlled-release membranes promises to be a potential therapeutic in preventing epidural scar formation after laminectomy.

Gas chromatography/atmospheric pressure chemical ionization/mass spectrometry for the analysis of organochlorine pesticides and polychlorinated biphenyls in human serum.

A method using a novel atmospheric pressure chemical ionization source for coupling gas chromatography (GC/APCI) to triple quadrupole mass spectrometry (MS/MS) for the determination of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) regulated by the Stockholm Convention is presented. One microliter injection of a six-point calibration curve of native PCBs and OCPs, ranging from 0.04 to 300pg/µL, was performed. The relative standard deviation (RSD) of the relative response factors (RRFs) was less than 15% with a coefficient of determination (r(2))>0.995. Meanwhile, two calibration solutions (CS), CS 2 (0.4pg/µL) and CS 3 (4pg/µL) were analyzed to study the repeatability calculated for both area and RRFs. The RSD for RRF ranged from 3.1 to 16% and 3.6 to 5.5% for CS 2 and CS 3, respectively. The limits of detection (LOD) determined by peak-to-peak signal-to-noise ratio (S/N) of 3 were compared between the GC/APCI/MS/MS and a GC coupled to high resolution mass spectrometry (GC/HRMS) system. GC/APCI/MS/MS resulted in lower LOD for most of the compounds, except for PCB#74, cis-chlordane and trans-chlordane. GC/APCI/MS/MS and GC/HRMS were also compared by performing analysis on 75 human serum samples together with eight QA/QC serum samples. The comparison between GC/APCI/MS/MS system and GC/HRMS system for 16 of the targeted compounds was carried out. No statistically significant difference was discovered. Due to increased sensitivity and user friendly operation under atmospheric pressure, GC/APCI/MS/MS is a powerful alternative technique that can easily meet the specification of GC/HRMS.

The metabolically healthy but obese phenotype is associated with lower plasma levels of persistent organic pollutants as compared to the metabolically abnormal obese phenotype.

CONTEXT: Although obesity is strongly linked to insulin resistance and type 2 diabetes, a subset of obese individuals termed metabolically healthy but obese (MHO) appears relatively protected from the development of cardiometabolic complications. The origins of this metabolically healthy phenotype remain unclear. Recently, persistent organic pollutants (POPs) have emerged as potential endocrine disruptors. OBJECTIVE: The aim of this study was to test the hypothesis that the MHO phenotype presents lower circulating levels of POPs as compared to the metabolically abnormal obese (MAO) phenotype. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of 76 nondiabetic obese (body mass index ≥30 kg/m(2)) postmenopausal women. MAIN OUTCOME MEASURES: Plasma concentrations of 21 POPs as well as cardiometabolic risk factors were analyzed. RESULTS: For similar age, body mass index, and fat mass index, MHO women (n = 40) showed higher insulin sensitivity levels and a more favorable cardiometabolic profile than MAO women (n = 36), as evidenced by a 2-fold increase in glucose disposal rates measured by the hyperinsulinemic-euglycemic clamp (P = .001). Among 18 detectable pollutants measured, MAO women had higher plasma concentrations of 12 POPs (fold increase, 1.4-2.9; P < .001-.036). Logistic regression analyses showed that the prevalence of the MAO phenotype was significantly associated with higher levels of total dioxin- and non-dioxin-like polychlorinated biphenyls (odds ratio, 4.7; 95% confidence interval, 1.8-12.5; P = .002), as well as trans-nonachlor (odds ratio, 6.1; 95% CI, 2.2-16.4; P < .001). CONCLUSION: Our study demonstrates that the metabolically healthy and abnormal phenotypes have distinct plasma POP profiles.