Publications (225) View all
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Article: Pharmaceuticals and personal care products in the environment: what are the big questions?
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ABSTRACT: Background: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment.Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas.Data sources: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance.Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f ) antibiotic resistance, and g) risk management.Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.Environmental Health Perspectives 05/2012; 120(9):1221-9. · 7.04 Impact Factor -
Article: A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows.
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ABSTRACT: The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazole inhibits the activity of two cytochrome P450s (CYPs) key to sex steroid production in vertebrates, CYP11a (cholesterol side chain cleavage) and CYP17 (c17α-hydroxylase/17, 20-lyase). Sexually mature fish were exposed to water-borne KTC (30 or 300 μg/L) in a flow-through system for up to 8d, following which animals were allowed to recover in clean water. Fish were sampled after 1, 4 and 8d of exposure, and after 1, 8 and 16d of recovery. A shorter-term time-course experiment also was conducted in which females were sampled on seven occasions during a 12h KTC exposure. Ketoconazole consistently depressed ex vivo gonadal synthesis of testosterone (T) in both sexes, and 17β-estradiol (E2) in females during both exposure and recovery phases of the time-course studies. Effects on ex vivo steroidogenesis in females occurred within as little as 1h of exposure. Plasma concentrations of T in males and E2 in females also were depressed by exposure to KTC, but these decreases did not persist to the same degree as observed for the ex vivo effects. In females, after decreases within 12h, plasma E2 concentrations were similar to (or greater than) controls at 24h of exposure, while in males, plasma T returned to levels comparable to controls within 1d of cessation of KTC exposure. The discrepancy between the ex vivo and in vivo data at later stages in the test is consistent with some type of compensatory response to KTC in fish. However, we were unable to ascertain the mechanistic basis for such a response. For example, although a number of genes related to steroid synthesis (e.g., cyp11a, cyp17) were up-regulated in the gonads of both males and females during the exposure and early recovery phases of the experiment, this did not seem to account for the resurgence in plasma steroid concentrations in KTC-exposed fish. Further studies focused on metabolism and clearance of steroids might lend insights as to the effects of KTC on plasma steroid concentrations. Overall, our results demonstrate the complex, temporally dynamic nature of the vertebrate HPG system in response to chemical stressors.Aquatic toxicology (Amsterdam, Netherlands) 02/2012; 114-115:88-95. · 3.12 Impact Factor -
Article: A graphical systems model and tissue-specific functional gene sets to aid transcriptomic analysis of chemical impacts on the female teleost reproductive axis.
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ABSTRACT: Oligonucleotide microarrays and other 'omics' approaches are powerful tools for unsupervised analysis of chemical impacts on biological systems. However, the lack of well annotated biological pathways for many aquatic organisms, including fish, and the limited power of microarray-based analyses to detect low level differential expression of individual genes can hinder the ability to infer and understand chemical effects based on transcriptomic data. Here we report on the supervised assembly of a series of tissue-specific functional gene sets intended to aid transcriptomic analysis of chemical impacts on the female teleost reproductive axis. Gene sets were defined based on an updated graphical systems model of the teleost brain-pituitary-gonadal-hepatic axis. Features depicted in the model were organized into gene sets and mapped to specific probes on three zebrafish (Danio rerio) and two fathead minnow (Pimephales promelas) microarray platforms. Coverage of target genes on the microarrays ranged from 48% for the fathead minnow arrays to 88% for the most current zebrafish platform. Additionally, extended fathead minnow gene sets, incorporating first degree neighbors identified from a Spearman correlation network derived from a large compendium of fathead minnow microarray data, were constructed. Overall, only 14% of the 78 genes queried were connected in the network. Among those, over half had less than five neighbors, while two genes, cyclin b1 and zona pellucida glycoprotein 3, had over 100 first degree neighbors, and were neighbors to one another. Gene set enrichment analyses were conducted using microarray data from a zebrafish hypoxia experiment and fathead minnow time-course experiments conducted with three different endocrine-active chemicals. Results of these analyses demonstrate the utility of the approach for supporting biological inference from ecotoxicogenomic data and comparisons across multiple toxicogenomic experiments. The graphical model, gene mapping, and gene sets described are now available to the scientific community as tools to support ecotoxicogenomic research.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2011; 746(2):151-62. · 2.85 Impact Factor -
Article: Effects of a glucocorticoid receptor agonist, dexamethasone, on fathead minnow reproduction, growth, and development.
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ABSTRACT: Synthetic glucocorticoids are pharmaceutical compounds prescribed in human and veterinary medicine as anti-inflammatory agents and have the potential to contaminate natural watersheds via inputs from wastewater treatment facilities and confined animal-feeding operations. Despite this, few studies have examined the effects of this class of chemicals on aquatic vertebrates. To generate data to assess potential risk to the aquatic environment, we used fathead minnow 21-d reproduction and 29-d embryo-larvae assays to determine reproductive toxicity and early-life-stage effects of dexamethasone. Exposure to 500 µg dexamethasone/L in the 21-d test caused reductions in fathead minnow fecundity and female plasma estradiol concentrations and increased the occurrence of abnormally hatched fry. Female fish exposed to 500 µg dexamethasone/L also displayed a significant increase in plasma vitellogenin protein levels, possibly because of decreased spawning. A decrease in vitellogenin messenger ribonucleic acid (mRNA) expression in liver tissue from females exposed to the high dexamethasone concentration lends support to this hypothesis. Histological results indicate that a 29-d embryo-larval exposure to 500 µg dexamethasone/L caused a significant increase in deformed gill opercula. Fry exposed to 500 µg dexamethasone/L for 29 d also exhibited a significant reduction in weight and length compared with control fry. Taken together, these results indicate that nonlethal concentrations of a model glucocorticoid receptor agonist can impair fish reproduction, growth, and development.Environmental Toxicology and Chemistry 12/2011; 31(3):611-22. · 2.81 Impact Factor -
Article: Proteomic analysis of zebrafish brain tissue following exposure to the pesticide prochloraz.
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ABSTRACT: The hypothalamus-pituitary-gonadal (HPG) axis plays a central role in the maintenance of homeostasis and disruptions in its function can have important implications for reproduction and other critical biological processes. A number of compounds found in aquatic environments are known to affect the HPG axis. In the present study, we used two-dimensional electrophoresis to investigate the proteome of female and male zebrafish brain after 96 h exposure to the fungicide prochloraz. Prochloraz has known effects on a number of key HPG molecules, including antagonism of Cyp17 and Cyp19 (aromatase). Twenty-eight proteins were shown to be differentially expressed in the brains of females and 22 in males. Proteins were identified using LC-MS/MS and identities were examined relative to brain function in the context of changing steroid hormone levels. There was little overlap between sexes in proteins exhibiting differential expression. Proteins with known roles in metabolism, learning, neuroprotection, and calcium regulation were determined to be differentially regulated. Relationships between identified proteins were also examined using Ingenuity Pathway Analysis, and females were shown to exhibit enrichment of several metabolic pathways. We used differentially expressed proteins to establish a putative classifier consisting of three proteins that was able to discriminate prochloraz-exposed from control females. Putatively impacted brain functions and specific protein changes that were observed have the potential to be generalized to other that similarly impact steroid hormone levels.Aquatic toxicology (Amsterdam, Netherlands) 08/2011; 105(3-4):618-28. · 3.12 Impact Factor
