A New Arrangement for the Anticancer Antibiotics Tallysomycin and Bleomycin When Bound to Zinc: An Assessment of Metal and Ligand Chirality by NMR and Molecular Dynamics

Bleomycin A2 (BLMA2, a clinically used drug) and tallysomycin A (TLMA) are two closely related anticancer antibiotics activated by O2 reaction with their Fe(II) complexes. Fe(II) can be modeled by Zn(II). Evidence obtained that the disaccharide and metal-binding domains of ZnTLMA and ZnBLMA2 are superimposable includes the following very similar NMR features:  the 1H and 13C NMR chemical shifts, the 1H and 13C chemical shift changes upon Zn(II) binding, and the NOESY spectra. We evaluated several ZnTLMA structural models with four and five ligating donor atoms from TLMA by using 2D NMR, NOESY back-calculation methods, and restrained molecular mechanics/molecular dynamics calculations. Our results are most consistent with ligation by five N donors, the β-aminoalanine (ALA) amines (NC2 and NC3), the pyrimidinylpropionamide (PRO) pyrimidine (NC10), and the β-hydroxyhistidine amide (NC12) and imidazole (NC29). Metal complexation to TLMA or BLMA2 creates newly stable chiral centers (the metal and the ALA secondary amine, NC3); for the first time, an extensive analysis of the chirality of both centers has been performed. A cross-peak between a PRO H and a disaccharide mannose H is clearly present in the low mixing time NOESY spectrum of ZnTLMA and in the published spectrum of ZnBLMA2. This cross-peak has led us to discover a novel square pyramid (sp) basket arrangement of the drug donor atoms, with PRO NC10 at the apex and SS chirality. A close variant, with donors adopting a trigonal bipyramidal (tbp) arrangement, gave results almost as satisfactory. Our findings raise interesting aspects relevant to drug activation. The literature suggests that the activated form is HO2Fe(III)BLMA2; the five N donors are in an SS-sp I arrangement, with the ALA primary amine (NC2) at the apex. If the Fe(II) form of the drugs had the SS-sp basket or SS-tbp arrangement, addition of O2 could yield products with the drug in an SS-sp I arrangement. Models with RR chirality, such as proposed previously for ZnBLMA2, are energetically unfavorable, cannot account for the NMR results, and cannot readily convert to the SS-sp I geometry. Unlike in RR models, the carbamoyl group of the mannose cannot bind to the metal in SS models. Instead, in our model the disaccharide covers the sixth binding site

Urinary Bisphenol A Concentrations in Relation to Serum Thyroid and Reproductive Hormone Levels in Men from an Infertility Clinic

Human exposure to bisphenol A (BPA) is widespread. Animal studies have demonstrated that BPA can alter endocrine function, but human studies are limited. For the present study, we measured urinary BPA concentrations and serum thyroid and reproductive hormone levels in 167 men recruited through an infertility clinic. BPA was detected in 89% of urine samples with a median (range) of 1.3 (2:T) and positively associated with follicle-stimulating hormone (FSH) and FSH:inhibin B ratio. Because BPA is metabolized quickly and multiple urine measures may better reflect exposure than a single measure, we also considered among a subset of the men the BPA concentrations in repeated urine samples collected weeks or months following serum sample collection. In these analyses, the effect estimates remained consistent for FSH and E2:T but were somewhat weakened for inhibin B. In addition, we observed inverse relationships between urinary BPA concentrations and free androgen index (ratio of testosterone to sex hormone binding globulin), estradiol, and thyroid stimulating hormone. Our results suggest that urinary BPA concentrations may be associated with altered hormone levels in men, but these findings need to be substantiated through further research

Specific-gravity–adjusted urinary MEP concentration according to combinations of product types used

<p><b>Copyright information:</b></p><p>Taken from "Personal Care Product Use Predicts Urinary Concentrations of Some Phthalate Monoesters"</p><p>Environmental Health Perspectives 2005;113(11):1530-1535.</p><p>Published online 18 Jul 2005</p><p>PMCID:PMC1310914.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p> Data points represent medians; error bars represent 25th and 75th percentiles

Isomer-Specific Serum Concentrations of Perfluorooctane Sulfonic Acid among U.S. Adults: Results from the National Health and Nutrition Examination Survey (NHANES) and the Study of Women’s Health Across the Nation Multi-Pollutant Study (SWAN-MPS)

Electrochemical fluorination manufacture of perfluorooctane sulfonic acid (PFOS), one of the most studied per- and polyfluoroalkyl substances, produces mixtures of linear and branched isomers, but little is known about human exposure to linear or branched PFOS isomers. We examined determinants affecting isomer-specific patterns of PFOS in serum in two adult populations in the United States, the National Health and Nutrition Examination Survey (NHANES) and the Study of Women’s Health Across the Nation Multi-Pollutant Study (SWAN-MPS). After adjusting for demographic variables, fish consumption (in both populations), a glomerular filtration rate above 90 mL/min/1.73 m2 (observed in NHANES; not tested in SWAN-MPS), premenopausal status (only observed in SWAN-MPS), and less consumption of processed food (observed in SWAN-MPS; not tested in NHANES) were associated with a higher proportion of linear PFOS. Non-Hispanic Black and Asian participants were likely to have a higher proportion of linear PFOS than non-Hispanic White participants in both populations. Our findings suggest that isomer-specific patterns of PFOS serum concentrations in humans vary depending on population characteristics that affect PFOS exposure and excretion. Consideration of specific PFOS isomers in future human biomonitoring and epidemiologic studies can provide useful insight to better understand PFOS exposure

Determination of 16 Phthalate Metabolites in Urine Using Automated Sample Preparation and On-line Preconcentration/High-Performance Liquid Chromatography/Tandem Mass Spectrometry

We developed an on-line solid-phase extraction (SPE) method, coupled with isotope dilution high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) and with automated sample preparation, to simultaneously quantify 16 phthalate metabolites in human urine. The method requires a silica-based monolithic column for the initial preconcentration of the phthalate metabolites from the urine and a silica-based conventional analytical column for the chromatographic separation of the analytes of interest. It uses small amounts of urine (100 μL), is sensitive (limits of detection range from 0.11 to 0.90 ng/mL), accurate (spiked recoveries are ∼100%), and precise (the inter- and intraday coefficients of variation are <10%). The method is not labor intensive, and, because pretreatment of the urine samples was performed automatically using an HPLC autosampler, involves minimal sample handling, thus minimizing exposure to hazardous chemicals. The method was validated on spiked, pooled urine samples and on urine samples from 43 adults with no known exposure to phthalates. The high sensitivity and high throughput (HPLC run time, including the preconcentration step, is 27 min) of this analytical method combined with the ease of use and effective automated sample preparation procedure make it suitable for large epidemiological studies to evaluate the prevalence of human exposure to phthalates

Specific-gravity–adjusted urinary MEP concentrations according to number of product types used

<p><b>Copyright information:</b></p><p>Taken from "Personal Care Product Use Predicts Urinary Concentrations of Some Phthalate Monoesters"</p><p>Environmental Health Perspectives 2005;113(11):1530-1535.</p><p>Published online 18 Jul 2005</p><p>PMCID:PMC1310914.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p> Data points represent medians; error bars represent 25th and 75th percentiles

Quantifying Phthalate Metabolites in Human Meconium and Semen Using Automated Off-Line Solid-Phase Extraction Coupled with On-Line SPE and Isotope-Dilution High-Performance Liquid Chromatography−Tandem Mass Spectrometry

We developed an analytical method using off-line solid-phase extraction (SPE) coupled with on-line SPE and isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (HPLC−MS/MS) to determine the concentrations of phthalate metabolites in human meconium and in semen. First, we used off-line SPE to remove interfering proteins and other biomolecules from the samples. Then, we preconcentrated the phthalate metabolites in the extract using on-line SPE before measuring them by HPLC−MS/MS. For most of the analytes, the limits of detection ranged between 0.2 and 0.7 ng/g for meconium and between 0.3 and 0.7 ng/mL for semen. The recovery after off-line SPE varied for most analytes between 65 and 99% at concentrations ranging from 3.0 to 30.0 ng/mL in semen and between 67 and 103% at concentrations ranging from 2.0 to 10.0 ng/mL in meconium. Precision measured by the relative standard deviation ranged from 3.2 to 19.1% for intraday and from 3.9 to 18.6% for interday. We validated this novel approachwhich is applicable to other biological matrixes, including serum and breast milkon spiked samples and on five meconium samples and one pooled semen sample from people with no known occupational exposure to phthalates

Trends in Exposure to Polyfluoroalkyl Chemicals in the U.S. Population: 1999−2008

Since 2002, practices in manufacturing polyfluoroalkyl chemicals (PFCs) in the United States have changed. Previous results from the National Health and Nutrition Examination Survey (NHANES) documented a significant decrease in serum concentrations of some PFCs during 1999−2004. To further assess concentration trends of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA), we analyzed 7876 serum samples collected from a representative sample of the general U.S. population ≥12 years of age during NHANES 1999−2008. We detected PFOS, PFOA, PFNA, and PFHxS in more than 95% of participants. Concentrations differed by sex regardless of age and we observed some differences by race/ethnicity. Since 1999−2000, PFOS concentrations showed a significant downward trend, because of discontinuing industrial production of PFOS, but PFNA concentrations showed a significant upward trend. PFOA concentrations during 1999−2000 were significantly higher than during any other time period examined, but PFOA concentrations have remained essentially unchanged during 2003−2008. PFHxS concentrations showed a downward trend from 1999 to 2006, but concentrations increased during 2007−2008. Additional research is needed to identify the environmental sources contributing to human exposure to PFCs. Nonetheless, these NHANES data suggest that sociodemographic factors may influence exposure and also provide unique information on temporal trends of exposure

Temporal Variability of Urinary Phthalate Metabolite Levels in Men of Reproductive Age-2

<p><b>Copyright information:</b></p><p>Taken from "Temporal Variability of Urinary Phthalate Metabolite Levels in Men of Reproductive Age"</p><p>Environmental Health Perspectives 2004;112(17):1734-1740.</p><p>Published online 16 Aug 2004</p><p>PMCID:PMC1253667.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Polybrominated Diphenyl Ethers and Biphenyl in Serum: Time Trend Study from the National Health and Nutrition Examination Survey for Years 2005/06 through 2013/14

Eleven polybrominated diphenyl ether (tri- to deca-BDE) congeners and 2,2′,4,4′,5,5′-hexabromobiphenyl (BB153) have been measured in pooled serum samples from the National Health and Nutrition Examination Survey (NHANES) for one decade (from survey years 2005/06 through 2013/14). The pools, which are representative of the general noninstitutionalized population of the United States, encompassed thirty-two demographic groups defined by sex, race/ethnicity (Mexican American, non-Hispanic black, non-Hispanic white, and all other race/ethnicities), and age (12–19, >20–39, >40–59, and ≥60 years). The adjusted geometric means were determined in a multiple linear regression model for the six congeners (BDE28, BDE47, BDE99, BDE100, BDE153, and BB153) with detectable concentrations in at least 60% of pools in each of the thirty-two demographic groups; the level of significance for all statistical comparisons thereof were determined. BDE154 and BDE209 were detected in 60% of the NHANES 2011/12 and 2013/14 pools; only these two survey periods were evaluated for these congeners. The percent change in concentration by a 2-year survey period was calculated. All examined PBDEs reported in five survey periods decreased in concentration, except BDE153, for which concentrations increased by 12.0% (95% CI 7.1–16.4) and 8.4% (95% CI 2.9–14.1) for the age groups 40–59 and ≥60 years, respectively; no significant change was observed in younger age groups. Excluding BDE153, we observed larger percentage decreases by a 2-year survey period for the age groups 12–19, 20–39, and ≥60 years compared with the age group 40–59 years. The percentage decrease by a two-year survey period ranged between −19.6% (BDE99, 20–39 years old) and −4.5% (BDE100, 40–59 years old). Although five polybrominated diphenyl ether (PDBE) congeners and BB153 are still frequently detected in the U.S. general population, PBDE concentrations have decreased since 2005–2006, likely, because of changes in manufacturing practices that started in the mid-2000s