Aptly chosen, effectively emphasizing the action and mechanism of antimycin A1.

Rhizoctonia solani Kühn, a plant pathogenic fungus that can cause diseases in multiple plant species is considered one of the common and destructive pathogens in many crops. This study investigated the action of antimycin A1, which was isolated from Streptomyces AHF-20 found in the rhizosphere soil of an ancient banyan tree, on Rhizoctonia solani and its mechanism. The inhibitory effect of antimycin A1 on R. solani was assessed using the comparative growth rate method. The results revealed that antimycin A1 exhibited a 92.55% inhibition rate against R. solani at a concentration of 26.66 µg/mL, with an EC50 value of 1.25 µg/mL. To observe the impact of antimycin A1 on mycelial morphology and ultrastructure, the fungal mycelium was treated with 6.66 µg/mL antimycin A1, and scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed. SEM analysis demonstrated that antimycin A1 caused mycelial morphology to become stripped, rough, and folded. The mycelium experienced severe distortion and breakage, with incomplete or locally enlarged ends, shortened branches, and reduced numbers. TEM observation revealed thickened cell walls, indistinct organelle boundaries, swollen mitochondria, exosmotic substances in vesicles, slow vesicle fusion, and cavitation. Real-time quantitative PCR and enzyme activity assays were conducted to further investigate the impact of antimycin A1 on mitochondria. The physiological and biochemical results indicated that antimycin A1 inhibited complexes III and IV of the mitochondrial electron transport chain. RT-PCR analysis demonstrated that antimycin A1 controlled the synthesis of relevant enzymes by suppressing the transcription levels of ATP6, ATP8, COX3, QCR6, CytB, ND1, and ND3 genes in mitochondria. Additionally, a metabolomic analysis revealed that antimycin A1 significantly impacted 12 metabolic pathways. These pathways likely experienced alterations in their metabolite profiles due to the inhibitory effects of antimycin A1. Consequently, the findings of this research contribute to the potential development of novel fungicides.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

What is in the fish? Collaborative trial in suspect and non-target screening of organic micropollutants using LC- and GC-HRMS.

A collaborative trial involving 16 participants from nine European countries was conducted within the NORMAN network in efforts to harmonise suspect and non-target screening of environmental contaminants in whole fish samples of bream (Abramis brama). Participants were provided with freeze-dried, homogenised fish samples from a contaminated and a reference site, extracts (spiked and non-spiked) and reference sample preparation protocols for liquid chromatography (LC) and gas chromatography (GC) coupled to high resolution mass spectrometry (HRMS). Participants extracted fish samples using their in-house sample preparation method and/or the protocol provided. Participants correctly identified 9-69 % of spiked compounds using LC-HRMS and 20-60 % of spiked compounds using GC-HRMS. From the contaminated site, suspect screening with participants' own suspect lists led to putative identification of on average ∼145 and ∼20 unique features per participant using LC-HRMS and GC-HRMS, respectively, while non-target screening identified on average ∼42 and ∼56 unique features per participant using LC-HRMS and GC-HRMS, respectively. Within the same sub-group of sample preparation method, only a few features were identified by at least two participants in suspect screening (16 features using LC-HRMS, 0 features using GC-HRMS) and non-target screening (0 features using LC-HRMS, 2 features using GC-HRMS). The compounds identified had log octanol/water partition coefficient (KOW) values from -9.9 to 16 and mass-to-charge ratios (m/z) of 68 to 761 (LC-HRMS and GC-HRMS). A significant linear trend was found between log KOW and m/z for the GC-HRMS data. Overall, these findings indicate that differences in screening results are mainly due to the data analysis workflows used by different participants. Further work is needed to harmonise the results obtained when applying suspect and non-target screening approaches to environmental biota samples.

Suspect and non-target screening of semi-volatile emerging contaminants in indoor dust from Danish kindergartens.

Indoor dust is a sink of hundreds of organic chemicals, and humans may potentially be exposed to these via indoor activities. This study investigated potentially harmful semi-volatile organic contaminants in indoor dust from Danish kindergartens using suspect and non-target screening on gas chromatography (GC)-Orbitrap, supported by target analyses using GC-low resolution mass spectrometry (LRMS). A suspect list of 41 chemicals with one or more toxicological endpoints, i.e. endocrine disruption, carcinogenicity, neurotoxicity and allergenicity, known or suspected to be present in indoor dust, was established including phthalate and non-phthalate plasticizers, flame retardants, bisphenols, biocides, UV filters and other plastic additives. Of these, 29 contaminants were detected in the indoor dust samples, also including several compounds that had been banned or restricted for years. In addition, 22 chemicals were tentatively identified via non-target screening. Several chemicals have not previously been detected in Danish indoor dust. Most of the detected chemicals are known to be potentially harmful for human health while hazard assessment of the remaining compounds indicated limited risks to human. However, children were not specifically considered in this hazard assessment.

Case report: A compound heterozygous mutations in ASNS broadens the spectrum of asparagine synthetase deficiency in the prenatal diagnosis.

Asparagine synthetase deficiency (ASNSD) is a rare congenital disorder characterized by severe progressive microcephaly, global developmental delay, spastic quadriplegia, and refractory seizures. ASNSD is caused by variations of the ASNS gene. The present study showed a Chinese family with a fetus suffering microcephaly. Whole-exome sequencing and Sanger sequencing were used to identify the disease-associated genetic variants. Compound heterozygous variants c.97C>T p. (R33C) and c.1031-2_1033del were identified in the ASNS gene and the variants were inherited from the parents. The mutation site c.97C>T was highly conserved across a wide range of species and predicted to alter the local electrostatic potential. The variant c.1031-2_1033del was classified pathogenic. However, there is no case report of prenatal diagnosis of ASNSD. This is the first description of fetal compound mutations in the ASNS gene leading to ASNSD, which expanded the spectrum of ASNSD.

Limb girdle muscular dystrophy 23 caused by compound heterozygous mutations of LAMA2 gene.

Introduction: Mutations of LAMA2 gene are associated with congenital muscular dystrophy (CMD). The LAMA2-related CMD mainly consists of two diseases, merosin deficient congenital muscular dystrophies type 1A (MDC1A) and limb girdle muscular dystrophy 23 (LGMD23). LGMD23 is characterized by slowly progressive proximal muscle weakness, which primarily affects the lower limbs and results in gait difficulties. Additional clinical features include increased serum creatine kinase, abnormal electromyography with or without white matter abnormalities on brain imaging. Methods: Clinical data were collected from a Chinese Han family. Whole-exome sequencing, Sanger sequencing, RT-PCR and TA clone sequencing were performed on the family members. Results: Compound heterozygous mutations of LAMA2: c.1693C > T (p. Q565*) (maternally inherited) and c.9212-6T > G (paternally inherited) were identified and confirmed in the proband. The mutation c.1693C > T (p. Q565*) was classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. By performing RT-PCR and TA clone sequencing, an insertion of 40-bp intronic sequence (intron 64) was found in the transcripts of the proband and her father, which resulted in a frameshift and premature truncation codon of the LAMA2. In particular, the variant truncated the LamG domain of the LAMA2. Therefore, the c.9212-6T>G was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. Discussion: Our findings described two novel mutations in a girl with LGMDR23, which contributes to the genetic counseling of the family and expands the clinical and molecular spectrums of the rare disease.

Paclitaxel induces pyroptosis by inhibiting the volume­sensitive chloride channel leucine­rich repeat­containing 8a in ovarian cancer cells.

Pyroptosis is a newly identified form of cell death, morphologically characterized by excessive cell swelling. In the present study, paclitaxel (PTX) combined with platinum were used as first­line chemotherapy, against ovarian cancer cells by inducing multiple types of cell death. However, it remains unclear whether PTX can induce pyroptosis in ovarian cancer cells. It was recently reported that PTX inhibited chloride channels, an inhibition known to cause cell swelling. In the present study, it was first verified that pyroptosis­like cell death, as well as cleaved­caspase­3 and cleaved­gasdermin E (GSDME) were induced by PTX in A2780 ovarian cancer cells. PTX inhibited the background­ and hypotonicity­activated chloride currents, promoted intracellular chloride ion accumulation, those manifestations are similar to those of the classic volume­regulatory anion channel (VRAC) blocker, 4­(2­butyl­6,7­dichloro­2­cy-clopentyl­indan­1­on5­yl) oxobutyric acid (DCPIB). Of note, both DCPIB and the downregulation of VRAC constituent protein leucine­rich repeat­containing 8a themselves could not induce persisted cell swelling and pyroptosis­like phenotypes. However, they could enhance the effects of PTX in inducing pyroptosis­like phenotypes, such as marked cell swelling, cell membrane rupture and excessive activation of caspase­3 and GSDME N­terminal fragment, which ultimately caused marked pyroptosis in A2780 cells. These findings revealed a potential mechanism of PTX and offered new insights into the effects of a synergistical combination of PTX and VRACs blockers in ovarian cancer chemotherapy.

Endocrine disrupting chemicals in indoor dust: A review of temporal and spatial trends, and human exposure.

Several chemicals with widespread consumer uses have been identified as endocrine-disrupting chemicals (EDCs), with a potential risk to humans. The occurrence in indoor dust and resulting human exposure have been reviewed for six groups of known and suspected EDCs, including phthalates and non-phthalate plasticizers, flame retardants, bisphenols, per- and polyfluoroalkyl substances (PFAS), biocides and personal care product additives (PCPs). Some banned or restricted EDCs, such as polybrominated diphenyl ethers (PBDEs), di-(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), are still widely detected in indoor dust in most countries, even as the predominating compounds of their group, but generally with decreasing trends. Meanwhile, alternatives that are also potential EDCs, such as bisphenol S (BPS), bisphenol F (BPF), decabromodiphenyl ethane (DBDPE) and organophosphate flame retardants (OPFRs), and PFAS precursors, such as fluorotelomer alcohols, have been detected in indoor dust with increasing frequencies and concentrations. Associations between some known and suspected EDCs, such as phthalate and non-phthalate plasticizers, FRs and BPs, in indoor dust and paired human samples indicate indoor dust as an important human exposure pathway. Although the estimated daily intake (EDI) of most of the investigated compounds was mostly below reference values, the co-exposure to a multitude of known or suspected EDCs requires a better understanding of mixture effects.

RTN2, a new member of circadian clock genes identified by database mining and bioinformatics prediction, is highly expressed in ovarian cancer.

Increasing evidence suggests that core circadian genes have major roles in the carcinogenic mechanisms of multiple human malignancies. Among these genes, the role of reticulon 2 (RTN2) in ovarian cancer (OV) has so far remained elusive. In the present study, circadian clock gene (CCG) aberrations were systematically assessed across malignancies by using Gene Expression Omnibus and The Cancer Genome Atlas data. The results indicated that various core clock genes (ULK1, ATF3, CRY2, CSF3R, DAAM2, GAS7, NPTXR, PPPIR15A and RTN2) had elevated levels in tumors in comparison with normal tissues and their low expression levels were associated with a better prognosis in OV, indicating that they may be potential candidates for novel investigational approaches. The mRNA and protein expression levels of RTN2 in OV were then further analyzed by reverse transcription­quantitative PCR and immunohistochemistry, respectively. The results indicated that RTN2 mRNA and protein levels were increased in OV specimens in comparison with control samples. Differentially expressed CCGs, such as RTN2, were suggested as indicators of asynchronous circadian rhythms in cancer, which may provide a theoretical basis for chrono­therapy.

From Spent Lithium-Ion Batteries to Low-Cost Li4SiO4 Sorbent for CO2 Capture.

The huge consumption of fossil fuels leads to excessive CO2 emissions, and its reduction has become an urgent worldwide concern. The combination of renewable energies with battery energy storage, and carbon capture, utilization, and storage are well acknowledged as two major paths in achieving carbon neutrality. However, the former route faces the discard problem of a large amount of lithium-ion batteries (LIBs) due to their limited lifespan, while it is costly to obtain effective CO2-capturing materials to put the latter into implementation. Herein, for the first time, we propose a route to synthesize low-cost Li4SiO4 as CO2 sorbents from spent LIBs, verify the technical feasibility, and evaluate the CO2 adsorption/desorption performance. The results show that Li4SiO4 synthesized from the cathode with self-reduction by the anode graphite of LIBs has a superior CO2 capacity and cyclic stability, which is constant at around 0.19 g/g under 15 vol % CO2 after 80 cycles. Moreover, the cost of fabricating sorbents from LIBs is only 1/20-1/3 of the conventional methods. We think this work can not only promote the recycling of spent LIBs but also greatly reduce the cost of preparing Li4SiO4 sorbents, and thus could be of great significance for the development of CO2 adsorption.

Acidic Electrolyzed Water Inhibits the Viability of Gardnerella spp. via Oxidative Stress Response.

The vaginal microbiota, dominated by Lactobacilli, plays an important role in maintaining women's health. Disturbance of the vaginal microbiota allows infection by various pathogens such as Gardnerella spp. (GS) and related anaerobic bacteria resulting in bacterial vaginosis (BV). At present, the treatment options for BV are extremely limited. Treatment of antibacterial drugs and vaginal acidification are the two primary therapeutic methods. Acid electrolyzed water (AEW) is known to inactivate microorganisms and is considered a medical application in recent years. Studies have found that Lactobacillus acidophilus (LA) probiotics helps to inhibit GS-induced BV. Our study took GS and LA as the research object, which aims to explore AEW as a potential alternative therapy for BV and its underlying mechanisms. We first obtained the pH of AEW (3.71-4.22) close to normal vaginal pH (3.8-4.5) to maintain normal vaginal acidification conditions. Plate counting experiments showed that AEW (pH: 4.07, ORP: 890.67, ACC: 20 ppm) (20 ppm) could better inhibit the viability of GS but had a more negligible effect on LA. Then, we preliminarily explored the possible mechanism of AEW anti-GS using cell biology experiments and transmission electron microscopy. Results showed that the membrane permeability was significantly increased and the integrity of cell membrane was destroyed by AEW in GS than those in LA. AEW also caused protein leakage and cell lysis in GS without affecting LA. Meanwhile, AEW induced a number of reactive oxygen species (ROS) production in GS, with no obvious LA changes. Finally, we found that 20 ppm AEW exhibited excellent antibacterial effect on the vaginal secretions of women diagnosed with BV by Amsel criteria and sialic acid plum method. Taken together, our findings manifest that 20 ppm AEW has an excellent antibacterial effect in GS with less effect on LA, which might be expected to become a potential therapy for BV.

Prenatal diagnosis of Walker-Warburg syndrome due to compound mutations in the B3GALNT2 gene.

BACKGROUND: Congenital hydrocephalus is one of the symptoms of Walker-Warburg syndrome that is attributed to the disruptions of the genes, among which the B3GALNT2 gene is rarely reported. A diagnosis of the Walker-Warburg syndrome depends on the clinical manifestations and the whole-exome sequencing after birth, which is unfavorable for an early diagnosis. METHODS: Walker-Warburg Syndrome was suspected in two families with severe fetal congenital hydrocephalus. Whole-exome sequencing and Sanger sequencing were performed on the affected fetuses. RESULTS: The compound heterozygous variants c.1A>G p.(Met1Val) and c.1151+1G>A, and c.1068dupT p.(D357*) and c.1052 T>A p.(L351*) in the B3GALNT2 gene were identified, which were predicted to be pathogenic and likely pathogenic, respectively. Walker-Warburg syndrome was prenatally diagnosed on the basis of fetal imaging and whole-exome sequencing. CONCLUSIONS: Our findings expand the spectrum of pathogenic mutations in Walker-Warburg syndrome and provide new insights into the prenatal diagnosis of the disease.

Excess iodide-induced reactive oxygen species elicit iodide efflux via ß-tubulin-associated ClC-3 in thyrocytes.

Iodide (I-) is crucial to thyroid function, and its regulation in thyrocytes involves ion transporters and reactive oxygen species (ROS). However, the extent of 2Cl-/H+ exchanger (ClC-3) involvement in the iodide (I-) efflux from thyrocytes remains unclear. Therefore, we examined the effects of ClC-3 on I- efflux. ClC-3 expression was found to significantly alter the serum TT3 and TT4 concentrations in mice. We further found that excess I- stimulation affected ClC-3 expression, distribution, and I- efflux in FRTL-5 cells. Immunofluorescence analyses indicated that ClC-3 mainly accumulated in the cell membrane and co-localized with ß-tubulins after 24 h of excess I- treatment, and that this process depended on ROS production. Thus, ClC-3 may be involved in I- efflux at the apical pole of thyrocytes via excess I--induced ROS production and ß-tubulin polymerization. Our results reveal novel insights into the role of ClC-3 in I- transport and thyroid function.

Disulfiram-copper activates chloride currents and induces apoptosis with tyrosine kinase in prostate cancer cells.

AIM: To elucidates the mechanism that disulfiram/copper complex (DSF/Cu) treatment activates chloride channels and induces apoptosis in prostate cancer cells. METHODS: Cellular membrane currents were measured by membrane clamp technique; western blot to detect protein expression; flow cytometry to detect apoptosis; immunofluorescence to detect target protein co-localization, and further validated by a combination of protein-protein interaction and mock protein molecular docking techniques. RESULTS: DSF/Cu activated chloride channels and induced apoptosis in LNCaP (a type of androgen-dependent prostate cancer cells) cells. The chloride currents activated by DSF/Cu were significantly reduced after knockdown of CLC3 with siRNA. In addition, DSF/Cu-activated chloride currents were reduced to background current levels after perfusion with genistein, a highly specific tyrosine kinase inhibitor. Conversely, DSF/Cu failed to activate chloride currents in LNCaP cells after 30 minutes of pre-incubation with genistein. When genistein was removed, and DSF/Cu was added, the activated currents were small and unstable, and gradually decreased. Immunofluorescence in LNCaP cells also showed co-localization of the CLC3 protein with tyrosine kinase 2ß (PTK2B). CONCLUSION: DSF/Cu can activate chloride channels and induce apoptosis in LNCaP cells with the involvement of tyrosine kinase. These results provide new insights into the target therapy of prostate cancer.

Sample preparation techniques for suspect and non-target screening of emerging contaminants.

The progress in sensitivity and resolution in mass spectrometers in recent years provides the possibility to detect a broad range of organic compounds in a single procedure. For this reason, suspect and non-target screening techniques are gaining attention since they enable the detection of hundreds of known and unknown emerging contaminants in various matrices of environmental, food and human sources. Sample preparation is a critical step before analysis as it can significantly affect selectivity, sensitivity and reproducibility. The lack of generic sample preparation protocols is obvious in this fast-growing analytical field, and most studies use those of traditional targeted analysis methods. Among them, solvent extraction and solid phase extraction (SPE) are widely used to extract emerging contaminants from solid and liquid sample types, respectively. Sequential solvent extraction and a combination of different SPE sorbents can cover a broad range of chemicals in the samples. Gel permeation chromatography (GPC) and adsorption chromatography, including acidification, are typically used to remove matrix components such as lipids from complex matrices, but usually at the expense of compound losses. Ideally, the purification of samples intended for non-target analysis should be selective of matrix interferences. Recent studies have suggested quality assurance/quality control measures for suspect and non-target screening, based on expansion and extrapolation of target compound lists, but method validations remain challenging in the absence of analytical standards and harmonized sample preparation approaches.

17ß-Estradiol activates Cl- channels via the estrogen receptor α pathway in human thyroid cells.

Estradiol regulates thyroid function, and chloride channels are involved in the regulation of thyroid function. However, little is known about the role of chloride channels in the regulation of thyroid functions by estrogen. In this study, the effects of estrogen on chloride channel activities in human thyroid Nthy-ori3-1 cells were therefore investigated using the whole cell patch-clamp technique. The results showed that the extracellular application of 17ß-estradiol (E2) activated Cl- currents, which reversed at a potential close to Cl- equilibrium potential and showed remarkable outward rectification and an anion permeability of I- > Br- > Cl- > gluconate. The Cl- currents were inhibited by the chloride channel blockers, NPPB and tamoxifen. Quantitative Real-time PCR results demonstrated that ClC-3 expression was highest in ClC family member in Nthy-ori3-1 cells. The down-regulation of ClC-3 expression by ClC-3 siRNA inhibited E2-induced Cl- current. The Cl- current was blocked by the estrogen receptor antagonist, ICI 182780 (fulvestrant). Estrogen receptor alpha (ERα) and not estrogen receptor beta was the protein expressed in Nthy-ori3-1 cells, and the knockdown of ERα expression with ERα siRNA abolished E2-induced Cl- currents. Estradiol can promote the accumulation of ClC-3 in cell membrane. ERα and ClC-3 proteins were partially co-localized in the cell membrane of Nthy-ori3-1 cells after estrogen exposure. The results suggest that estrogen activates chloride channels via ERα in normal human thyroid cells, and ClC-3 proteins play a pivotal role in the activation of E2-induced Cl- current.

Occupational Exposures to Phthalates among Black and Latina U.S. Hairdressers Serving an Ethnically Diverse Clientele: A Pilot Study.

Hairdressers may be differentially exposed to phthalates through hair salon services provided and products used, yet no U.S. studies have investigated these exposures in this population. We characterized concentrations and exposure determinants to nine phthalate metabolites in postshift urine samples among 23 hairdressers from three Black and three Dominican salons, as well as a comparison group of 17 female office workers from the Maryland/Washington D.C. metropolitan area. Overall, hairdressers had higher metabolite concentrations than office workers. The geometric mean (GM) for monoethyl phthalate (MEP) was 10 times higher in hairdressers (161.4 ng/mL) than office workers (15.3 ng/mL). Hairdressers providing select services and using certain products had higher GM MEP concentrations than those who did not: permanent waves/texturizing (200.2 vs 115.4 ng/mL), chemical straightening/relaxing (181.6 vs 92.1 ng/mL), bleaching (182.3 vs 71.6 ng/mL), permanent hair color (171.9 vs 83.2 ng/mL), and Brazilian blowout/keratin treatments (181.4 vs 134.6 ng/mL). Interestingly, hairdressers providing natural services had lower GM MEP concentrations than those who did not: twists (129.1 vs 215.8 ng/mL), sister locs/locs (86.0 vs 241.9 ng/mL), and afros (94.7 vs 203.9 ng/mL). Larger studies are warranted to confirm our findings and identify disparities in occupational phthalate exposures.

Evidence of increased estrogenicity upon metabolism of Bisphenol F - Elucidation of the key metabolites.

The increasing concern over bisphenol A (BPA) has directed much attention toward bisphenol F (BPF) and bisphenol S (BPS) as BPA alternatives for the development of "BPA-free" products. Consequently, BPS and BPF were frequently detected in surface water, sediment, sewage effluent, indoor dust, and even in food and biological fluids in humans. Thus, environmental researches start to focus on the potential environmental risks of BPA alternatives. While the estrogenically active metabolites and the specific estrogenically active structure are still unknown. In this study, the MTT assay on acute cytotoxicity and the recombinant transactivation assay were carried out to determine whether BPF and BPS are suitable alternatives to BPA. Our results show that the cytotoxic and estrogenic activities of BPS and BPF are lower than those of BPA. However, after the addition of a rat liver homogenate to simulate mammal metabolism, BPF exhibited higher estrogenic activity than BPA. To identify the chemical structures and estrogen receptor binding affinities of active estrogenic metabolites, LC-MS, MetaPrint2D(-React), and VirtualToxLab were integrated. The observed results indicated that the para-hydroxylated BPF and BPF-OCH3 might have strong ER binding affinities. These results demonstrate that metabolization is important to consider upon investigating endocrine disruption of chemicals getting into contact with humans, such as in dental sealing or food packaging. Alternatives to potentially hazardous substances should be thoroughly tested prior to use.

Determinants of phthalate exposure among a U.S.-based group of Latino workers.

BACKGROUND: Phthalates are endocrine disrupting compounds linked to various adverse health effects. U.S. national biomonitoring data indicate that select minority subgroups may suffer disparate exposures to phthalates. Still, exposures and their respective determinants among these subgroups are not well characterized. OBJECTIVE: We sought to examine determinants of phthalate exposure in a subsample of US-based Latino adults. METHODS: We conducted a cross-sectional study on 94 Latino immigrant adults in Maryland. Participants were >18 years of age and working in a service-based industry. We administered an interviewer-administered questionnaire to capture information on potential exposure determinants (e.g., demographic characteristics, consumer product use, and workplace exposures and behaviors) and using HPLC/MS-MS we quantified concentrations of 9 urinary phthalate metabolites: monoethyl phthalate (MEP, diethyl phthalate metabolite); mono-n-butyl phthalate (MBP, di-n-butyl phthalate metabolite); mono-isobutyl phthalate (MiBP, di-isobutyl phthalate metabolite; monobenzyl phthalate (MBzP, benzylbutyl phthalate metabolite); molar sum of di-2-ethylhexyl phthalate or DEHP metabolites [mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECCP)]; and mono(3-carboxypropyl) phthalate (MCPP, a non-specific metabolite of several phthalates including di-n-butyl phthalate and di-n-octyl phthalate). DEHP was analyzed as the molar sum of four metabolites (ΣDEHP = MEHP + MEHHP + MECPP + MEOHP). Spearman correlations, Wilcoxon-Mann-Whitney, and Kruskal-Wallis tests were conducted to assess bivariate associations between metabolite concentrations and potential exposure determinants. Covariates associated with metabolites at p < 0.10 in bivariate analyses were included in multivariable linear regression models to assess the independent effects of predictors on metabolite concentrations. RESULTS: Uncorrected median phthalate metabolite concentrations were lower in our study population (50% of samples ranged between 1.4 and 23.6 µg/L. While we observed some significant associations with select predictors in our bivariate analysis, select associations were attenuated in multivariable regression models. In our final multivariable linear regression models, we found that use of bleach (ß = 1.15, 95%CI:0.30, 2.00) and consumption pasta/rice/noodles (ß = 0.87, 95%CI: 0.27, 1.46) was positively associated with MBzP concentrations. MEP concentrations were inversely associated with use of furniture polish (ß = -1.17, 95%CI: 2.21, -0.12) and use of scented dryer sheets (ß = -1.08, 95%CI: 2.01, -0.14). Lastly, ΣDEHP concentrations were inversely associated with use of degreaser (ßDEHP = -0.65, 95%CI: 1.25, -0.05). CONCLUSIONS: In this predominantly U.S.-based Central American subsample of adults, we observed lower metabolite concentrations than those previously reported in other U.S. studies and other countries. Our findings could be due, in part, to temporal trends in phthalate exposures and cultural differences related to exposure-related behaviors. While some exposure determinants were identified in our bivariate analyses, results from multivariable regression models did not provide clear results as many associations were attenuated. Environmental exposures may vary within minority subgroups and should be explored further in future studies to further inform exposure mitigation strategies.

ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells.

Epithelial ovarian cancers (EOC) present as malignant tumors with high mortality in the female reproductive system diseases. Acquired resistance to paclitaxel (PTX), one of the first-line treatment of EOC, remains a therapeutic challenge. ClC-3, a member of the voltage-gated Cl- channels, plays an essential role in a variety of cellular activities, including chemotherapeutic resistance. Here, we demonstrated that the protein expression and channel function of ClC-3 was upregulated in PTX resistance A2780/PTX cells compared with its parental A2780 cells. The silence of ClC-3 expression by siRNA in A2780/PTX cells partly recovered the PTX sensitivity through restored the G2/M arrest and resumed the chloride channel blocked. ClC-3 siRNA both inhibited the expression of ClC-3 and ß-tubulin, whereas the ß-tubulin siRNA reduced the expression of itself only, without affecting the expression of ClC-3. Moreover, treatment of ClC-3 siRNA in A2780/PTX cells increased the polymerization ratio of ß-tubulin, and the possibility of proteins interaction between ClC-3 and ß-tubulin was existing. Take together, the over-expression of ClC-3 protein in PTX-resistance ovarian cancer cells promotes the combination of ClC-3 and ß-tubulin, which in turn increase the ration of free form and decrease the quota of the polymeric form of ß-tubulin, and finally reduce the sensitivity to PTX. Our findings elucidated a novel function of ClC-3 in regulating PTX resistance and ClC-3 could serve as a potential target to overcome the PTX resistance ovarian cancer.