Synthesis of gem-Difluorinated Oxa/Azaspiro[2.4]heptanes via Palladium-Catalyzed Spirocyclopropanation.

A palladium-catalyzed spirocyclopropanation of gem-difluoroalkenes with π-allylpalladium 1,4-dipoles has been successfully developed, which gives a powerful and straightforward synthetic strategy for the construction of novel gem-difluorinated spirocyclic compounds, 6,6-difluoro-5-oxa/azaspiro[2.4]heptanes. The scope of gem-difluoroalkenes can be extended to styrenes, acrylic esters, and acrylamides to realize the installment of various functional groups and different heteroatoms on the spirocyclic skeletons, which could be converted to valuable compounds with potential biological activity. The mechanistic investigations revealed the competition between spirocyclopropanation and ß-F elimination of π-allylpalladium zwitterionic intermediates.

Effects of the SEMA4B gene on hexavalent chromium [Cr(VI)]-induced malignant transformation of human bronchial epithelial cells.

Our previous study identified the potential of SEMA4B methylation level as a biomarker for hexavalent chromium [Cr(VI)] exposure. This study aimed to investigate the role of the SEMA4B gene in Cr(VI)-mediated malignant transformation of human bronchial epithelial (BEAS-2B) cells. In our population survey of workers, the geometric mean [95% confidence intervals (CIs)] of Cr in blood was 3.80 (0.42, 26.56) µg/L. Following treatment with various doses of Cr(VI), it was found that 0.5 µM had negligible effects on the cell viability of BEAS-2B cells. The expression of SEMA4B was observed to decrease in BEAS-2B cells after 7 days of treatment with 0.5 µM Cr(VI), and this downregulation continued with increasing passages of Cr(VI) treatment. Chronic exposure to 0.5 µM Cr(VI) enhanced the anchorage-independent growth ability of BEAS-2B cells. Furthermore, the use of a methylation inhibitor suppressed the Cr(VI)-mediated anchorage-independent growth in BEAS-2B cells. Considering that Cr levels exceeding 0.5 µM can be found in human blood due to occupational exposure, the results suggested a potential carcinogenic risk associated with occupational Cr(VI) exposure through the promotion of malignant transformation. The in vitro study further demonstrated that Cr(VI) exposure might inhibit the expression of the SEMA4B gene to promote the malignant transformation of BEAS-2B cells.

An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu-VTAGABA-VTADA-ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.

Palladium-catalyzed ring-opening [5+2] annulation of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acids: rapid synthesis of 7-membered lactones.

A novel approach for the synthesis of unsaturated 7-membered lactones by Pd-catalyzed [5+2] dipolar cycloaddition of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acid derivatives has been developed. Various Meldrum's acid derivatives worked well in this reaction under mild reaction conditions. A variety of 7-membered lactones can be accessed in a facile manner in moderate to good yields by employing easily prepared Meldrum's acid derivatives.

Molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes: a novel strategy for catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles.

A novel strategy for the catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles bearing a wide range of functional groups in good to excellent yields by non-noble molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes is described. The salient features of the transformation include the use of readily available substrates, valuable products and ease of scale-up. The mechanistic study indicates that the reaction occurred via double deoxygenation by the Mo(VI)/Mo(IV) catalytic cycle from 2-nitroazobenzene, through the formation of 2-aryl-2H-benzo[d][1,2,3]triazole-N1-oxide or nitrene intermediates.

Independent and Combined Associations of Blood Manganese, Cadmium and Lead Exposures with the Systemic Immune-Inflammation Index in Adults.

Manganese (Mn), cadmium (Cd) and lead (Pb) have toxic effects on the immune system. However, their independent and combined effects on immune-inflammation responses are unclear. In recent years, the systemic immune-inflammation index (SII) has been developed as an integrated and novel inflammatory indicator. A retrospective cross-sectional study of 2174 adults ≥20 years old from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 was conducted. Generalized linear models were used to evaluate the independent and combined associations of SII with blood Mn, Cd and Pb levels. As continuous variables, both blood Cd and Mn showed dose-dependent relationships with the SII before and after adjusting for all potential confounding factors. Metal concentrations were then converted into categorical variables. Compared with the adults in the lowest Cd or Mn tertile, those in the highest tertile had higher risks of elevated SII. Furthermore, co-exposure to Mn and Cd also showed a positive relationship with the SII after adjusting for all confounding factors. However, the single effect of Pb exposure and the joint effect of Pb and other metal exposures on the SII were not observed. This study provides important epidemiological evidence of the associations of SII with single and co-exposure effects of blood Mn, Cd, and Pb.

Hexavalent chromium [Cr(VI)]-induced ribosomal DNA copy number variation and DNA damage responses and their associations with nucleolar protein HRAS in humans and cells.

The carcinogenicity of hexavalent chromium [Cr(VI)] and its compounds has been widely recognized, yet the mechanism of genetic damage is still not fully understood. The ribosomal DNA (rDNA) copy number is recently considered a potential marker of cancer-associated stress. To investigate the roles of rDNA copy number variation (CNV) in DNA damage responses (DDRs) induced by Cr(VI) and the potential mechanism from nucleolar protein HRAS, a cross-sectional study in Cr(Ⅵ)-exposed workers and an in vitro experiment using HeLa cells were conducted. Our results showed increased levels of rDNA CNV, DDRs, and HRAS expression in Cr(VI)-exposed workers. Generalized linear regression analyses showed that Cr(VI) exposure was significantly positively associated with increased levels of rDNA CNV, DDRs, and HRAS expression in Cr(VI)-exposed workers. Moreover, there were pairwise associations between rDNA CNV, DDRs, and HRAS levels. Mediation analyses found that rDNA CNV significantly mediated the association between Cr(VI) exposure and DDRs. The in vitro experiments further confirmed that Cr(VI) treatment induced increased levels of rDNA CNV, DDRs, and HRAS expression in HeLa cells. Cr(VI)-induced rDNA CNV, ATM activation, and apoptosis damage were then strongly enhanced by HRAS depletion with siRNA in vitro, suggesting the important role of HRAS in CNV and DDRs caused by Cr(VI). The combined results of the human and cell line studies indicated that Cr(VI) exposure might enhance rDNA CNV by regulation of HRAS expression, which leads to Cr(VI)-induced genetic damage.

The Hypervelocity Impact Behavior and Energy Absorption Evaluation of Fabric.

In this work, the mechanical behavior and energy absorption characteristics of flexible fabric under hypervelocity impact (HVI) were investigated. Basalt fabric, ultra-high molecular weight polyethylene (UHMWPE) fabric, and aluminum alloy (Al) plate were chosen to be the sample materials for their excellent mechanical properties and applicative prospect in spacecraft shielding. HVI experiments had been conducted with the help of a two-stage light-gas gun facility, wherein Al projectile with 3.97 mm diameter was launched at velocities in the range 4.1~4.3 km/s. Impact conditions and areal density were kept constant for all targets. The microstructural damage morphology of fiber post-impact was characterized using a scanning electron microscope (SEM). Analysis results show that a brittle fracture occurred for Basalt fiber during HVI. On the contrary, the ductile fractures with large-scale plastic deformation and apparent thermal softening/melting of the material had happened on the UHMWPE fiber when subjected to a projectile impact. According to the HVI shielding performance and microstructural damage analysis results, it can be inferred that ductile fractures and thermal softening/melting of the material were the prevailing energy absorption behaviors of UHMWPE fabric, which leads to absorbing more impact energy than Basalt fabric and eventually, contributes the superior shielding performance.

Association of Dietary α-Carotene and ß-Carotene Intake with Low Cognitive Performance in Older Adults: A Cross-Sectional Study from the National Health and Nutrition Examination Survey.

This study aims to examine the relationships of dietary α-carotene and ß-carotene intake with cognitive function. The data were selected from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. A total of 2009 participants were included in this analysis. Dietary α-carotene and ß-carotene intake were averaged by two 24-h dietary recalls. The Consortium to Establish a Registry for Alzheimer's Disease Word Learning subset (CERAD W-L), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST) were used to evaluate cognitive function. Logistic regression and restricted cubic spline models were applied to explore the associations of dietary α-carotene and ß-carotene intake with cognitive performance. After adjusting for all confounding factors, compared with individuals in the lowest quartile of ß-carotene dietary intake, those in the highest quartile had lower risks of both CERAD W-L decline [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.44-0.90] and AFT decline (OR = 0.66, 95% CI: 0.47-0.94). In addition, the third quartile of ß-carotene dietary intake had a significantly decreased risk of lower DSST (OR = 0.67, 95% CI: 0.48-0.83). Compared with the lowest quartile of α-carotene intake, the OR of AFT decline in the highest intake quartile was 0.66 (95% CI: 0.46, 0.94). For males, both dietary α-carotene and ß-carotene intake were associated with a decreased risk of AFT decline (OR = 0.42, 95% CI: 0.25-0.71; OR = 0.51, 95% CI: 0.30-0.85, respectively). For females, dietary α-carotene intake was associated with a decreased risk of CERAD W-L decline (OR = 0.55, 95% CI: 0.33-0.91) and dietary ß-carotene intake was associated with decreased risks of both CERAD W-L and AFT decline (OR = 0.37, 95% CI: 0.21-0.64; OR = 0.58, 95% CI: 0.37-0.91, respectively). Our results suggested that higher dietary α-carotene and ß-carotene intake had inverse effects on cognitive function decline among older adults.

Systemic immune-inflammation index is associated with decreased bone mass density and osteoporosis in postmenopausal women but not in premenopausal women.

Purpose: This study aims to investigate the associations of the systemic immune-inflammation index (SII) with bone mineral density (BMD) and osteoporosis in adult females from a nationally representative sample. Methods: A cross-sectional study was performed among 4092 females aged ≥20 years from the National Health and Nutrition Examination Survey 2007-2010. Linear and logistic regressions were applied to explore the relationships of SII with BMD and the risk of osteoporosis, respectively. Results: Linear regression analyses found that a doubling of SII levels was significantly correlated with a 1.39% (95% CI: 0.57%, 2.20%) decrease in total femur BMD, a 1.16% (95% CI: 0.31%, 2.00%) decrease in femur neck BMD, a 1.73% (95% CI: 0.78%, 2.66%) decrease in trochanter BMD, and a 1.35% (95% CI: 0.50%, 2.20%) decrease in intertrochanteric BMD among postmenopausal women, after adjusting for covariates. Logistic regression analyses showed that compared with postmenopausal women in the lowest SII quartile, those in the highest quartile had higher risks of osteoporosis in the total femur (odds ratio (OR) = 1.70, 95% CI: 1.04, 2.76), trochanter (OR = 1.86, 95% CI: 1.07, 3.38), intertrochanter (OR = 2.01, 95% CI: 1.05, 4.04) as well as overall osteoporosis (OR = 1.57, 95% CI: 1.04, 2.37). In contrast, there was no significant association between SII and BMD in premenopausal women. Conclusions: SII levels were negatively associated with BMD levels in postmenopausal women but not in premenopausal women. Elevated SII levels could be a potential risk factor for osteoporosis in postmenopausal women.

A soybean sodium/hydrogen exchanger GmNHX6 confers plant alkaline salt tolerance by regulating Na+/K+ homeostasis.

Alkaline soil has a high pH due to carbonate salts and usually causes more detrimental effects on crop growth than saline soil. Sodium hydrogen exchangers (NHXs) are pivotal regulators of cellular Na+/K+ and pH homeostasis, which is essential for salt tolerance; however, their role in alkaline salt tolerance is largely unknown. Therefore, in this study, we investigated the function of a soybean NHX gene, GmNHX6, in plant response to alkaline salt stress. GmNHX6 encodes a Golgi-localized sodium/hydrogen exchanger, and its transcript abundance is more upregulated in alkaline salt tolerant soybean variety in response to NaHCO3 stress. Ectopic expression of GmNHX6 in Arabidopsis enhanced alkaline salt tolerance by maintaining high K+ content and low Na+/K+ ratio. Overexpression of GmNHX6 also improved soybean tolerance to alkaline salt stress. A single nucleotide polymorphism in the promoter region of NHX6 is associated with the alkaline salt tolerance in soybean germplasm. A superior promoter of GmNHX6 was isolated from an alkaline salt tolerant soybean variety, which showed stronger activity than the promoter from an alkaline salt sensitive soybean variety in response to alkali stress, by luciferase transient expression assays. Our results suggested soybean NHX6 gene plays an important role in plant tolerance to alkaline salt stress.

Intakes of Folate, Vitamin B6, and Vitamin B12 in Relation to All-Cause and Cause-Specific Mortality: A National Population-Based Cohort.

The evidence regarding the intake of dietary folate, vitamin B6, and vitamin B12 in relation to mortality in the general population is limited. This study aimed to examine the relationship between dietary intakes of folate, vitamin B6, and vitamin B12 in relation to all-cause and cause-specific mortality in a large U.S. cohort. This study included a total of 55,569 adults from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 1999-2014. Vital data were determined by linking with the National Death Index records through 31 December 2015. Cox proportional hazards models were used to investigate the relationships of all-cause and cause-specific mortality with dietary folate, vitamin B6, and vitamin B12 intake. Dietary intakes of folate and vitamin B6 were inversely associated with mortality from all-cause, cardiovascular disease, and cancer for men and with mortality from all-cause and cardiovascular disease for women. In men, the multivariable hazard ratios (95% confidence intervals) for the highest versus lowest quintiles of folate and vitamin B6 were 0.77 (0.71-0.85) and 0.79 (0.71-0.86) for all-cause mortality, 0.59 (0.48-0.72) and 0.69 (0.56-0.85) for CVD mortality, and 0.68 (0.56-0.84) and 0.73 (0.60-0.90) for cancer mortality, respectively. Among women, the multivariable hazard ratios (95% confidence intervals) for the highest versus lowest quintiles of folate and vitamin B6 were 0.86 (0.78-0.95) and 0.88 (0.80-0.97) for all-cause mortality and 0.53 (0.41-0.69) and 0.56 (0.44-0.73) for CVD mortality, respectively. No significant associations between dietary vitamin B12 and all-cause and cause-specific mortality were observed. In conclusion, higher dietary intakes of folate and vitamin B6 were significantly associated with lower all-cause and cardiovascular mortality. Our findings suggest that increasing the intake of folate and vitamin B6 may lower the mortality risk among U.S. adults.

Synaptotagmin-1 is a bidirectional Ca2+ sensor for neuronal endocytosis.

Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exocytosis­endocytosis coupling in neurons and nonneuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported; however, Ca2+ inhibition in endocytosis remains debatable with unknown mechanisms. Here, we show that synaptotagmin-1 (Syt1), the primary Ca2+ sensor initiating exocytosis, plays bidirectional and opposite roles in exocytosis­endocytosis coupling by promoting slow, small-sized clathrin-mediated endocytosis but inhibiting fast, large-sized bulk endocytosis. Ca2+-binding ability is required for Syt1 to regulate both types of endocytic pathways, the disruption of which leads to inefficient vesicle recycling under mild stimulation and excessive membrane retrieval following intense stimulation. Ca2+-dependent membrane tubulation may explain the opposite endocytic roles of Syt1 and provides a general membrane-remodeling working model for endocytosis determination. Thus, Syt1 is a primary bidirectional Ca2+ sensor facilitating clathrin-mediated endocytosis but clamping bulk endocytosis, probably by manipulating membrane curvature to ensure both efficient and precise coupling of endocytosis to exocytosis.

Associations between pyrethroid exposure and serum sex steroid hormones in adults: Findings from a nationally representative sample.

BACKGROUND: Pyrethroids have been considered as potential endocrine-disrupting chemicals and have been shown to be associated with endocrine-related health outcomes. However, limited studies directly explored the link between pyrethroid exposure and sex hormones in the general population. OBJECTIVES: To explore the associations between exposure to pyrethroids and serum sex steroid hormones in adults. METHODS: We evaluated the cross-sectional associations in 1235 adults aged ≥20 years who had been assigned to the National Health and Nutrition Examination Survey (NHANES) 2013-2014. The urinary concentration of 3-phenoxybenzoic acid (3-PBA) was applied as a biomarker of human pyrethroid exposure levels. Information on sex steroid hormones, including total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) in serum were measured. Free androgen index (FAI) and the ratio of TT to E2 (TT/E2) were also calculated. The percent changes with 95% confidence intervals (CIs) for a doubling of 3-PBA concentrations in the serum sex hormone levels were estimated using generalized linear regression models. RESULTS: The overall median concentrations of creatinine-adjusted 3-PBA were 0.58 µg/g creatinine, and 90.0% of adults had a detectable level of 3-PBA. In females, every two-fold increase in 3-PBA was associated with 4.34% (95% CI: 1.58%, 7.18%) higher levels of TT and 4.05% (95% CI: 7.03%, 1.16%) higher levels of SHBG, respectively. In males, a doubling in 3-PBA was associated with 3.02% (95% CI: 1.21%, 4.86%) increase in SHBG but 1.85% (-3.59%, -0.07%) decrease in FAI, respectively. In addition, significant non-linear associations of 3-PBA with SHBG in both males and females and TT in females were observed. CONCLUSIONS: Environmental pyrethroid exposure was associated with altered sex hormones in adults. This study provides important epidemiological evidence for the association of pyrethroids with endocrine disruption.

An aryl thiol-vinyl azide coupling reaction and a thiol-vinyl azide coupling/cyclization cascade: efficient synthesis of ß-ketosulfides and arene-fused 5-methylene-2-pyrrolidinone derivatives.

The addition reaction of thiol to vinyl azide has been extensively studied. Variously substituted aryl thiols are all viable for this coupling process. The scope of the other partner is successfully expanded from α-aryl vinyl azide to α-alkyl vinyl azide. A thiol-vinyl azide coupling/cyclization cascade is realized with substituted aryl vinyl azides carrying a 2-methoxycarbonyl group. The value of ß-ketosulfide products was demonstrated by its application in S-heterocycle synthesis.

Intranasal levels of lead as an exacerbation factor for allergic rhinitis in humans and mice.

BACKGROUND: Air pollutants are suspected to affect pathological conditions of allergic rhinitis (AR). OBJECTIVES: After detecting Pb (375 µg/kg) in Japanese cedar pollen, the effects of intranasal exposure to Pb on symptoms of AR were investigated. METHODS: Pollen counts, subjective symptoms, and Pb levels in nasal epithelial lining fluid (ELF) were investigated in 44 patients with Japanese cedar pollinosis and 57 controls from preseason to season. Effects of intranasal exposure to Pb on symptoms were confirmed by using a mouse model of AR. RESULTS: Pb levels in ELF from patients were >40% higher than those in ELF from control subjects during the pollen season but not before the pollen season. Pb level in ELF was positively associated with pollen counts for the latest 4 days before visiting a hospital as well as scores of subjective symptoms. Intranasal exposure to Pb exacerbated symptoms in allergic mice, suggesting Pb as an exacerbation factor. Pb levels in ELF and nasal mucosa in Pb-exposed allergic mice were higher than those in Pb-exposed nonallergic mice, despite intranasally challenging the same amount of Pb. Because the increased Pb level in the nasal mucosa of Pb-exposed allergic mice was decreased after washing the nasal cavity, Pb on the surface of but not inside the nasal mucosa may have been a source of increased Pb level in ELF of allergic mice. CONCLUSIONS: Increased nasal Pb level partially derived from pollen could exacerbate subjective symptoms of AR, indicating Pb as a novel hazardous air pollutant for AR.

Low-level environmental lead and cadmium exposures and dyslipidemia in adults: Findings from the NHANES 2005-2016.

BACKGROUND: Previous experimental and occupational health studies have shown the toxic effects of relatively high-level cadmium and lead on lipid metabolism. However, limited studies investigated the relationships between serum lipid levels and exposure to low-level lead and cadmium in adults. OBJECTIVE: To investigate the associations between lead and cadmium levels in blood and dyslipidemia in adults. METHODS: A retrospective cross-sectional study of 7,457 adults aged 20-79 years who were recruited in the National Health and Nutrition Examination Survey (NHANES, 2005-2016) was conducted. Multivariate linear and logistic regressions were used to examine the associations of blood lead and cadmium levels with serum lipid profiles and risk of dyslipidemia, respectively. RESULTS: The weighted geometric means [95% confidence intervals (CIs)] of lead and cadmium in blood were 1.23 (1.21, 1.25) µg/dL and 0.36 (0.35, 0.37) µg/L, respectively. Blood lead was significantly associated with serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (Apo B) levels after adjusting for covariates. Compared with the adults in the lowest blood lead quartile (≤0.76 µg/dL), those in the highest lead quartile (>1.90 µg/dL) had higher risks of elevated TC (OR = 1.88, 95% CI: 1.59-2.22), non-HDL-C (OR = 1.59, 95% CI: 1.33-1.91), LDL-C (OR = 1.68, 95% CI: 1.41-1.99) and Apo B (OR = 2.00, 95% CI: 1.46-2.73). However, the single effect of cadmium exposure and the joint effect of lead and cadmium exposures on dyslipidemia were not observed. CONCLUSION: Blood lead well below the current recommended level was positively associated with the risk of dyslipidemia in adults, while the low-level cadmium exposure currently observed in adults did not show any significant associations with lipid levels.

Association between exposure to polyfluoroalkyl chemicals and increased fractional exhaled nitric oxide in adults.

BACKGROUND: Perfluoroalkyl chemicals (PFCs) are widely detected in the environment and human body, and they have been linked to asthma and a number of respiratory responses in children and mice. However, no previous studies have investigated the association between exposure to PFCs and airway inflammation in adults. OBJECTIVES: To evaluate the associations between serum PFCs and fractional exhaled nitric oxide (FeNO), a biomarker of airway inflammation, in adults. METHODS: A cross-sectional study of 3630 adults aged 20-79 years who participated in the National Health and Nutrition Examination Survey (NHANES, 2007-2012) was conducted. Serum concentrations of five major PFCs were measured using SPE-HPLC-TIS-MS/MS method, including perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorodecanoic acid (PFDE). The detection rates of them were all >85%. Weighted multivariable linear regression and Bayesian kernel machine regression (BKMR) analyses were applied to examine the associations between serum PFCs and FeNO. RESULTS: After adjusted for potential confounding factors, linear regression analyses found that compared with their lowest tertiles, highest tertiles of PFOS, PFDE and PFOA were significantly associated with 5.02% (95% CI: 1.40%, 8.77%), 3.77% (95% CI: 0.30%, 7.36%) and 6.34% (95% CI: 2.81%, 10.01%) increases in FeNO, respectively. The second tertile of PFNA was significantly correlated with a 4.79% (95% CI: 1.41%, 8.29%) increase in FeNO compared with the lowest tertile. In the BKMR analysis, the mixture effect of PFCs on FeNO increased significantly when the PFC levels were at or above the 60th percentiles compared to those at their medians. PFOS and PFOA displayed significant positive single-exposure effects on FeNO when all the other PFCs are set at a particular threshold. CONCLUSIONS: This study provided preliminary evidence that serum PFCs were positively associated with increased FeNO in adults.