Phthalate exposure among US women, NHANES 1999--2002: Relationship to serum gonadotropin levels

Phthalates are industrial chemicals used primarily as plasticizers though they and are found in a myriad of consumer goods such as children's toys, food packaging, dental sealants, cosmetics, pharmaceuticals, perfumes, and building materials. US biomonitoring data show more than 75% of the population have exposure to mono-n-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-(2-ethyl) hexyl phthalate (MEHP), and mono-benzyl phthalate (MBZP). Reproductive toxicity from phthalate exposure in animal models has raised concerns about similar effects on fertility in humans. This dissertation research focuses on phthalate exposures in the US population and investigates the plausibility of an exposure-response relationship between phthalates and endocrine hormones essential for ovulation among US women. The objective of this research is to determine the relationship between levels of gonadotropins, follicle stimulating hormone (FSH) and leutinizing hormone (LH), and urinary phthalate monoester metabolites: MBP, MEP, MEHP, MBZP among National Health and Nutrition Examination Survey (NHANES) 1999-2002 women aged 35 to 60 years. Using biomarker data from a one-third sub-sample of NHANES participants, log transformed serum FSH and serum LH, respectively were regressed on phthalates controlling for age, body mass index, smoking, and creatinine taking into consideration the complex survey design (n=385). Models were stratified by reproductive status: reproductive (n=185), menopause transition (n=49) and post-menopausal (n=125). A decrease in FSH associated with increasing MBzP (beta=-0.094, p<0.05) was observed for all participants but no statistical association between log FSH and MBP, MEP, or MEHP was seen. A decrease in LH (beta=-0.125, p<0.05) was also observed with increasing MBzP for all participants though there was no relationship between levels of LH and MBP, MEP, or MEHP. The observed associations between FSH, LH and MBzP did not persist when stratified by reproductive status. Thus, the present study shows a change in endocrine hormones related to ovulation with increasing urinary MBzP among a representative sample of US women from 1999-2002 though this observed exposure-response relationship does not remain after stratification by reproductive status. ^

Dietary intake patterns and relationships to polybrominated diphenyl ether (PBDE) and phthalate body burden

Polybrominated diphenyl ethers (PBDEs) and phthalates are chemicals of concern because of high levels measured in people and the environment as well as the demonstrated toxicity in animal studies and limited epidemiological studies. Exposure to these chemicals has been associated with a range of toxicological outcomes, including developmental effects, behavioral changes, endocrine disruption, effects on sexual health, and cancer. Previous research has shown that both of these classes of chemicals contaminate food in the United States and worldwide. However, how large a role diet plays in exposure to these chemicals is currently unknown. To address this question, an exploratory analysis of data collected as part of the 2003-04 National Health and Nutrition Examination Survey (NHANES) was conducted. Associations between dietary intake (assessed by 24-hour dietary recalls) for a range of food types (meat, poultry, fish, and dairy) and levels PBDEs and phthalate metabolites were analyzed using multiple linear regression modeling. Levels of individual PBDE congeners 28, 47, 99, 100 as well as total PBDEs were found to be significantly associated with the consumption of poultry. Metabolites of di-(2-ethylhexyl) phthalate (DEHP) were found to be associated with the consumption of poultry, as well as with an increased consumption of fat of animal origin. These results, combined with results from previous studies, suggest that diet is an important route of intake for both PBDEs and phthalates. Further research needs to be conducted to determine the sources of food contamination with these toxic chemicals as well as to describe the levels of contamination of US food in a large, representative sample.^

(Table 1) Concentrations of phthalates in chloroform extracts from waters of the Northwest Indian Ocean and the Red Sea

Chloroform extracts of water-soluble organic matter collected in the water column from the surface to the bottom were studied by C-13 and H-1 NMR chromatographic mass spectrometry, and phthalate concentrations were determined by capillary gas-liquid chromatography. More than 14 compounds were found including diethyl phthalate, ethyl butyl phthalate, dibutyl phthalate, and di-2-ethylhexyl phthalate, phthalates with normal C4-C12 chains, phthalates partially esterified with methanol, and others, at total concentrations up to 0.4 mg/l. Possible reasons for presence of phthalates in oceans, sometimes in high concentrations, are discussed.

Seasonal variations in surface metabolite composition of Fucus vesiculosus and Fucus serratus sampled at outer Kiel Fjord (August 2012 - July 2013)

The chemical composition of surface associated metabolites of two Fucus species (Fucus vesiculosus and Fucus serratus) was analysed by means of gas chromatography-mass spectrometry (GC-MS) to describe temporal patterns in chemical surface composition. Method: The two perennial brown macroalgae F. vesiculosus and F. serratus were sampled monthly at Bülk, outer Kiel Fjord, Germany (54°27'21 N / 10°11'57 E) over an entire year (August 2012 - July 2013). Per month and species six non-fertile Fucus individuals were collected from mixed stands at a depth of 0.5 m under mid water level. For surface extraction approx. 50 g of the upper 5-10 cm apical thalli tips were cut off per species. The surface extraction of Fucus was performed according to the protocol of de Nys and co-workers (1998) with minor modifications (see Rickert et al. 2015). GC/EI-MS measurements were performed with a Waters GCT premier (Waters, Manchester, UK) coupled to an Agilent 6890N GC equipped with a DB-5 ms 30 m column (0.25 mm internal diameter, 0.25 mM film thickness, Agilent, USA). The inlet temperature was maintained at 250°C and samples were injected in split 10 mode. He carrier gas flow was adjusted to 1 ml min-1. Alkanes were used for referencing of retention times. For further details (GC-MS sample preparation and analysis) see the related publication (Rickert et al. submitted to PLOS ONE).

Y Trinuclear Cu-II structural isomers coordination, magnetism, electrochemistry and catalytic activity towards the oxidation of alkanes

The reaction of the Schiff base (3,5-di-tert-butyl-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H3L) with copper(II) nitrate, acetate or metaborate has led to the isomeric complexes [Cu-3(L)(2)(MeOH)(4)] (1), [Cu-3(L)(2)(MeOH)(2)]2MeOH (2) and [Cu-3(L)(2)(MeOH)(4)] (3), respectively, in which the ligand L exhibits dianionic (HL2-, in 1) or trianionic (L3-, in 2 and 3) pentadentate 1O,O,N:2N,O chelation modes. Complexes 1-3 were characterized by elemental analysis, IR spectroscopy, single-crystal X-ray crystallography, electrochemical methods and variable-temperature magnetic susceptibility measurements, which indicated that the intratrimer antiferromagnetic coupling is strong in the three complexes and that there exists very weak ferromagnetic intermolecular interactions in 1 but weak antiferromagnetic intermolecular interactions in both 2 and 3. Electrochemical experiments showed that in complexes 1-3 the Cu-II ions can be reduced, in distinct steps, to Cu-I and Cu-0. All the complexes act as efficient catalyst precursors under mild conditions for the peroxidative oxidation of cyclohexane to cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone, leading to overall yields (based on the alkane) of up to 31% (TON = 1.55x10(3)) after 6 h in the presence of pyrazinecarboxylic acid.

PPAR-mediated activity of phthalates: A link to the obesity epidemic?

The endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in wildlife and humans. Many of these chemicals may interact with members of the nuclear receptor superfamily. Peroxisome proliferator-activated receptors (PPARs) are such candidate members, which interact with many different endogenous and exogenous lipophilic compounds. More particularly, the roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named "metabolic disrupters". Phthalates are abundant environmental micro-pollutants in Europe and North America and may belong to this class. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.

Interference of pollutants with PPARs: endocrine disruption meets metabolism.

The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

Phthalates in the NICU: Is it safe?

AIMS: As growing concerns exist regarding phthalate exposure, which could be teratogenic, carcinogenic or induce reproductive toxicity, we aimed to review the evidence of the risks due to the use of medical devices containing di(2-ethylhexyl)phthalate in hospitalized neonates. METHODS: We reviewed the literature, searching through medical literature databases (Pubmed, MEDLINE, EBM reviews, Cochrane database, Embase and Google Scholar) using the following keywords: phthalate, di(2-ethylhexyl)phthalate, newborn and neonate. RESULTS: We identified several associations with short and long term health dangers, mainly subfertility, broncho-pulmonary dysplasia, necrotising enterocolitis, parenteral nutrition associated cholestasis and neuro-developmental disorders. These data are based mainly on animal or observational human studies. CONCLUSION: Clinicians must be aware of the potential risks due to phthalate exposure in the NICU. Di(2-ethylhexyl)phthalate containing materials should be identified and alternative devices should be considered. There is a need to improve knowledge in this area.

Synthesis and characterization of oxovanadium (IV) dithiocarbamates with pyridine

We report the synthesis and study of a new series of oxovanadium (IV) dithiocarbamate adducts and derivatives with pyridine and cyclohexyl, di-iso-butyl, di-n-propyl, anilin, morpholin, piperidin and di-iso-propyl amines. The complexes have been characterized by analytical, magnetochemical, IR, visible-UV spectral and thermal studies, and are assigned the formulas [VO(L)2].py, where L=cyclohexyl, di-iso-butyl, di-n-propyl, anilin dithiocarbamate and [VO(OH)(L)(py)2]OH.H2O (L=morpholin, piperidin and di-iso-propyl dithiocarbamate). The effect of the adduct formation on the pV=0 bound is discussed in terms of the IR (V=O, V-S and V-N stretching frequencies) and electronic spectra (d-d transitions).

APROVEITAMENTO DE RESÍDUO DE BIODIESEL PARA PREPARAÇÃO DE CARVÕES ÁCIDOS COM ELEVADA ATIVIDADE CATALÍTICA NA REAÇÃO DE ETERIFICAÇÃO DO GLICEROL

Environmentally friendly acid carbon (CG) catalysts, containing a high amount of sulfonated and oxygenated groups, were prepared from glycerin, a biodiesel waste. CGs were produced by glycerin carbonization in the presence of H2SO4 at 1:3 m:m ratio in a closed autoclave at 180ºC for different times: 0.25; 1; 3 and 6 hours (CG-0.25h; CG-1h; CG-3h and CG-6h, respectively). The catalyst properties for all carbons were evaluated in the glycerol etherification reaction with tert-butyl alcohol (TBA). The yield for mono-tert-butyl glycerol (MTBG), di-tert-butyl glycerol (DTBG) and tri-tert-butyl-glycerol (TTBG) was high and very similar for all CGs, of about 43% and 20% for the MTBG and DTBG + TTBG, respectively. Furthermore, the activity of these catalysts were close to those obtained using a commercial resin, Amberlyst-15, of about 50% and 27% for MTBG and DTBG + TTBG, respectively.

Evaluation of antioxidants stability by thermal analysis and its protective effect in heated edible vegetable oil

In this work, through the use of thermal analysis techniques, the thermal stabilities of some antioxidants were investigated, in order to evaluate their resistance to thermal oxidation in oils, by heating canola vegetable oil, and to suggest that antioxidants would be more appropriate to increase the resistance of vegetable oils in the thermal degradation process in frying. The techniques used were: Thermal Gravimetric (TG) and Differential Scanning Calorimetry (DSC) analyses, as well as an allusion to a possible protective action of the vegetable oils, based on the thermal oxidation of canola vegetable oil in the laboratory under constant heating at 180 ºC/8 hours for 10 days. The studied antioxidants were: ascorbic acid, sorbic acid, citric acid, sodium erythorbate, BHT (3,5-di-tert-butyl-4-hydroxytoluene), BHA (2, 3-tert-butyl-4-methoxyphenol), TBHQ (tertiary butyl hydroquinone), PG (propyl gallate) - described as antioxidants by ANVISA and the FDA; and also the phytic acid antioxidant and the SAIB (sucrose acetate isobutyrate) additive, which is used in the food industry, in order to test its behavior as an antioxidant in vegetable oil. The following antioxidants: citric acid, sodium erythorbate, BHA, BHT, TBHQ and sorbic acid decompose at temperatures below 180 ºC, and therefore, have little protective action in vegetable oils undergoing frying processes. The antioxidants below: phytic acid, ascorbic acid and PG, are the most resistant and begin their decomposition processes at temperatures between 180 and 200 ºC. The thermal analytical techniques have also shown that the SAIB antioxidant is the most resistant to oxidative action, and it can be a useful choice in the thermal decomposition prevention of edible oils, improving stability regarding oxidative processes.

Identification of fatty foods with contamination possibilities by plasticizers when stored in PVC film packaging

Poly-(vinyl chloride) (PVC) requires the addition of plasticizers - additives that give flexibility and malleability for its processing into flexible film. The most used ones are: di-(2-ethylhexyl) adipate (DEHA) and di-(2-ethylhexyl) phthalate (DEHP). Toxic effects of DEHP have been observed by several authors. Phthalates are being replaced by alternative substances in PVC flexible products, because of their possible toxicological effects. DEHA is a substitute for phthalates widely used as a plasticizer in PVC materials for involving food. Some authors have shown that the exposure to DEHA also induces toxicity. A cross-sectional study was performed to identify which fatty foods carry the possibility of contamination by DEHP and DEHA. Eighteen different foods with at least 3% (m/m) fat and the possibility of being wrapped in plastic film were determined. This study suggested that all foods were subject to contamination by DEHP and DEHA in those conditions - in decreasing consumption order of 96 to 22% in the convenience sample. New guidelines on the limits of DEHA and DEHP established by the Brazilian legislation, as additives in PVC film for packaging fatty food, are still relevant to ensure human health.

Oxovanadium(V) complexes of bis(phenolate) ligands with acetylacetone as co-ligand: synthesis, crystal structure, electrochemical and kinetics studies on the oxidation of ascorbic acid

Two vanadium(V) complexes, [VO(L-1)]acac)] (1) and [VO(L-2)(acac)] (2), where H2L1 = N,N-bis(2-hydroxy-3-5-di-tert-butyl-benzyl)propylamine and H2L2 = 2,2'-selenobis(4,6-di-tert-butylphenol), have been synthesized and characterized by elemental analyses, IR, V-51 NMR, both in the solid and in solution, and cyclic voltammetric studies. Single crystal X-ray studies reveal that in complex 1 the vanadium atom is octahedrally coordinated with an O5N donor environment, where the oxygen atom of the V-V=O moiety and the N atom of the ONO ligand occupy the axial sites while two oxygen atoms (O1 and O2) from the bisphenolate ligand and two oxygen atoms (O3 and O4) from the acac ligand occupy the equatorial plane. A similar bonding pattern has also been encountered for 2 with the exception that a Se atom instead of N is involved in weak bonding to the metal center. Both complexes showed reversible cyclic voltammeric responses and E-1/2 appears at -0.18 and 0.10 V versus NHE for complexes 1 and 2, respectively. The kinetics of oxidation of ascorbic acid by complex 1 were carried out in 50% MeCN-50% HO (v/v) at 25 degrees C. The high formation constant value, Q = 63 +/- 7 M-1, reveals that the reaction proceeds through the rapid formation of a H-bonded intermediate. The low k(2)Q(2)/k(1)Q(1) ratio (13.4) for 1 points out that there is extensive H-bonding between the oxygen atom of the V-V=O group and the OH group of ascorbic acid. (c) 2007 Published by Elsevier Ltd.

A square-planar nickel(II) monoradical complex with a bis(salicylidene)diamine ligand

The new square-planar Ni-II-N2O2 complex [Ni(L-Me)] (1(Me)), where L-Me, stands for the dianionic phenolato form of N,N'bis(3,5-di-tert-butyl-salicylidene)-4,5-dimethyl-1,2-phenyl- enediamine ((LH2)-L-Me), has been synthesised and fully characterised. X-ray crystallography was also used for the characterisation. The electrochemical one-electron oxidation of 1(Me) produces the thermally stable (within the temperature range 10-295 K) cationic species (1(Me))(+). The UV/Vis and X-band EPR experimental data, supported by DFT calculations, indicate that (1(Me))(+), is best described as a Ni-II monoradical complex and, thus, does NOT exist in a Ni-III ground state, in contrast to its demethylated counterpart [Ni(L-H)](+) (1(H))(+) below 170 K.

Effects of phthalic acid esters on the liver and thyroid

The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.