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Mills L.J.,U.S. Environmental Protection Agency | Henderson W.M.,Ecosystems Research Division | Jayaraman S.,U.S. Environmental Protection Agency | Gutjahr-Gobell R.E.,U.S. Environmental Protection Agency | And 3 more authors.
Environmental Toxicology | Year: 2015

Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget species (i.e., a fish), (2) compare biologically-active metabolites across species, (3) assess whether in vitro assays predict in vivo results, and (4) investigate metabolomic profiles in tamoxifen-treated fish to better understand the biological mechanisms of tamoxifen toxicity. In reproductive assays, tamoxifen exposure caused a significant reduction in egg production and significantly increased ovarian aromatase activity in spawning adult cunner fish (Tautogolabrus adspersus). In plasma from tamoxifen-exposed cunner, the predominant metabolite was 4-hydroxytamoxifen, while in rats it was N-desmethyltamoxifen. Because 4-hydroxytamoxifen is a more biologically active metabolite than N-desmethyltamoxifen, this difference could result in a different level of risk for the two species. The results of in vitro assays with fish hepatic microsomes to assess tamoxifen metabolism did not match in vivo results, indicating probable differences in excretion of tamoxifen metabolites in fish compared with rats. For the first time, a complete in vitro characterization of the metabolism of tamoxifen using fish microsomes is presented. Furthermore, a metabolomic investigation of cunner gonad extracts demonstrates that tamoxifen alters the biochemical profile in this nontarget species. Understanding the consequence of tamoxifen exposure in nontarget species, and assessing the discrepancies between sex- and species-mediated endpoints, is a step toward understanding how to accurately assess the risks posed by EAPs, such as tamoxifen, in the aquatic environment. © 2015 Wiley Periodicals, Inc. Source

Pleil J.D.,NERL | Stiegel M.A.,NERL | Sobus J.R.,NERL | Tabucchi S.,University of Pisa | And 2 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Humans experience chronic cumulative trace-level exposure to mixtures of volatile, semi-volatile, and non-volatile polycyclic aromatic hydrocarbons (PAHs) present in the environment as by-products of combustion processes. Certain PAHs are known or suspected human carcinogens and so we have developed methodology for measuring their circulating (blood borne) concentrations as a tool to assess internal dose and health risk. We use liquid/liquid extraction and gas chromatography-mass spectrometry and present analytical parameters including dynamic range (0-250 ng/ml), linearity (>0.99 for all compounds), and instrument sensitivity (range 2-22 pg/ml) for a series of 22 PAHs representing 2-6-rings. The method is shown to be sufficiently sensitive for estimating PAHs baseline levels (typical median range from 1 to 1000 pg/ml) in groups of normal control subjects using 1-ml aliquots of human plasma but we note that some individuals have very low background concentrations for 5- and 6-ring compounds that fall below robust quantitation levels. Source

Sharlin D.S.,University of Massachusetts Amherst | Gilbert M.E.,NHEERL | Taylor M.A.,NHEERL | Taylor M.A.,U.S. National Institutes of Health | And 4 more authors.
Journal of Neuroendocrinology | Year: 2010

Thyroid hormone is essential for normal brain development, although the degree to which the developing brain is sensitive to small perturbations in serum thyroxin is not clear. An important concept related to this is that the developing brain possesses potent mechanisms to compensate for low serum thyroid hormone, and this concept is routinely employed in discussions concerning clinical treatments or public health. However, experimental studies have not directly tested whether (or the degree to which) putative compensatory mechanisms can ameliorate the consequences of small reductions in serum thyroxin (T4). To formally test this concept, we employed a model of graded T4 reductions using doses of propylthiouracil (PTU) that were 200- to 67-fold lower than the dose traditionally used to produce hypothyroidism in rats. PTU produced a stepwise decrease in serum total T4, and a stepwise increase in serum thyroid-stimulating hormone (TSH), in type 2 deiodinase mRNA expression and enzyme activity in the brain, and in the expression of the mRNA encoding the tri-iodothyronine (T3) transporter MCT8 in the postnatal day (P) 15 cortex. However, the mRNA encoding RC3/neurogranin, a direct target of T3 action, exhibited a strong negative linear correlation with serum total T4 despite these adaptive responses. In addition, single-cell analysis of RC3 mRNA levels in cortical neurones demonstrated that the co-expression of MCT8 did not alter the relationship between RC3 mRNA and serum T4. These findings do not support the currently envisioned concept of the developing brain being capable of compensating for low T4. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd. Source

Alava P.,National Exposure Research Laboratory | Bradham K.,National Exposure Research Laboratory | Kohan M.,National Exposure Research Laboratory | Thomas D.J.,National Exposure Research Laboratory | And 4 more authors.
One Century of the Discovery of Arsenicosis in Latin America (1914-2014): As 2014 - Proceedings of the 5th International Congress on Arsenic in the Environment | Year: 2014

In sulfide-rich environments, methylated thioarsenicals form from corresponding methylated oxyarsenicals. The metabolic fate of these methylated thioarsenicals is unknown. Human arsenic (3+ oxidation state) methyltransferase (AS3MT) catalyzes transfer of a methyl group from S-adenosyl-methionine (AdoMet) to an arsenical substrate. To date, all identified substrates for AS3MT-catalyzed methylation are oxyarsenicals that contain arsenic in the trivalent oxidation state; thus, MMMTA and MMDTA, which contain arsenic in the pentavalent oxidation state, are unlikely candidates for AS3MT-catalyzed methylation. Using anaerobic conditions to prevent oxidation of thioarsenicals, MMMTA or MMDTA were added to reaction mixtures containing AS3MT, AdoMet, and the non-thiol reductant TCEP. Reaction products were separated by ion-exchange chromatography and detected by ICP-MS. Incubation of MMMTA with AS3MT yields dimethylmonothioarsenate (DMMTA) and dimethyl oxy arsenate (DMAV) as the primary metabolites while having MMAIII as intermediate metabolite. Production of MMAIII suggests that thiolated arsenicals are reduced and are not direct substrates for AS3MT. © 2014 Taylor & Francis Group. Source

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