Effects of gemfibrozil on lipid metabolism, steroidogenesis, and reproduction in the fathead minnow (<i>Pimephales promelas</i>)

Skolness, Sarah Y.; Durhan, Elizabeth J.; Jensen, Kathleen; Kahl, Michael D.; Makynen, Elizabeth A.; Villeneuve, Daniel L.; Ankley, Gerald T.

doi:10.1002/etc.1989

Cited by 40 publications

(14 citation statements)

References 48 publications

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“…It is also difficult to fully interpret studies where tissue, as opposed to plasma, concentrations of a drug have been measured (for example: diclofenac, 72 antidepressants, 73 gemfibrozil, 74 oxazapam, 28 ). Therefore, the suggestion that bluntnose minnow ( Pimephales notatus ) is up to an order of magnitude more sensitive to ibuprofen than humans, based on gill ibuprofen concentrations and the effect on prostaglandin E 2 synthesis, 75 must be viewed with caution.…”

Section: Apparent Limitations Of the Approach—studies That Appear Notmentioning

confidence: 99%

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

Rand‐Weaver

Margiotta-Casaluci

Patel

et al. 2013

Environ. Sci. Technol.

179

155

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Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.

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Section: Apparent Limitations Of the Approach—studies That Appear Notmentioning

confidence: 99%

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

Rand‐Weaver

Margiotta-Casaluci

Patel

et al. 2013

Environ. Sci. Technol.

179

155

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“…R. Soc. B 369: 20140022 [24,27,30,31] anti-androgens androgen receptor antagonism -impaired ovulation and spawning -impaired sexual differentiation -decreased nest defence -reproductive impairment -reduced probability of young of year survival** [32 -37] hormonal contraceptive oestrogen receptor activation -impaired ovulation and spawning -impaired sexual development -reproductive impairment [27] hormonal contraceptive oestrogen receptor antagonism* -impaired vitellogenesis, ovulation and spawning -impaired sexual differentiation -reproductive impairment** [38 -42] hormonal contraceptive progesterone receptor activation -reduced fecundity -reduced sperm motility -reproductive impairment [43 -46] anti-inflammatory glucocorticoid receptor activation -reduced oestradiol synthesis and fecundity -morphological abnormalities -decreased immune response -reproductive impairment -reduced probability of young of year survival** [47 -49] anti-depressants serotonin reuptake inhibition -morphological abnormalities -reduced fecundity -decreased food intake -impaired predator avoidance -reproductive impairment -reduced probability of young of year survival** [50 -55] anti-convulsant gamma-aminobutyric-acid receptor opening** sodium-channel inhibition -impaired predator avoidance -reduced probability of young of year survival** [56,57] non-steroidal anti-inflammatory drugs cyclooxygenase inhibition -impaired growth -impaired hatching -decreased spawning behaviour a -reduced fecundity a -increased probability of mortality** -reduced probability of young of year survival** -impaired reproduction a [58 -60] fibrates peroxisome proliferator-activated receptor activation -reduced fecundity -impaired reproduction [61] beta-blockers beta-adrenergic receptor antagonist -reduced growth -reduced probability of young of year survival** -increased probability of mortality** [62 -64] Aromatase inhibition is an established molecular initiating event for propiconazole, however other conazoles have been shown to inhibit other cytochrome P450 enzymes [76].…”

Section: (B) Conservation Of Molecular Target For Cross-species Extramentioning

confidence: 99%

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

LaLone

Berninger

Villeneuve

et al. 2014

Phil. Trans. R. Soc. B

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Medicinal innovation has led to the discovery and use of thousands of human and veterinary drugs. With this comes the potential for unintended effects on non-target organisms exposed to pharmaceuticals inevitably entering the environment. The impracticality of generating whole-organism chronic toxicity data representative of all species in the environment has necessitated prioritization of drugs for focused empirical testing as well as field monitoring. Current prioritization strategies typically emphasize likelihood for exposure (i.e. predicted/measured environmental concentrations), while incorporating only rather limited consideration of potential effects of the drug to non-target organisms. However, substantial mammalian pharmacokinetic and mechanism/mode of action (MOA) data are produced during drug development to understand drug target specificity and efficacy for intended consumers. An integrated prioritization strategy for assessing risks of human and veterinary drugs would leverage available pharmacokinetic and toxicokinetic data for evaluation of the potential for adverse effects to non-target organisms. In this reiview, we demonstrate the utility of read-across approaches to leverage mammalian absorption, distribution, metabolism and elimination data; analyse cross-species molecular target conservation and translate therapeutic MOA to an adverse outcome pathway(s) relevant to aquatic organisms as a means to inform prioritization of drugs for focused toxicity testing and environmental monitoring.

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“…In Japanese medaka (5 mg/L) and rainbow trout (46–152 mg/kg/d, Oncorhynchus mykiss ), gemfibrozil induced fatty acyl‐coenzyme A oxidase . In fathead minnows exposed to 600 µg/L gemfibrozil for 8 d, plasma cholesterol levels decreased and several hepatic genes involved in lipid metabolism were altered . However, when fish were exposed for 21 d, no effects on plasma cholesterol and triglycerides were detected.…”

Section: Introductionmentioning

confidence: 99%

Effects of triclocarban, N,N‐diethyl‐meta‐toluamide, and a mixture of pharmaceuticals and personal care products on fathead minnows (Pimephales promelas)

Zenobio

Sanchez

Archuleta

et al. 2014

Enviro Toxic and Chemistry

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Pharmaceuticals and personal care products (PPCPs) have been detected widely in aquatic ecosystems, but little is known about their mechanisms of toxicity. We exposed adult fathead minnows (Pimephales promelas) for 48 h to triclocarban (1.4 µg/L), N,N-diethyl-meta-toluamide (DEET; 0.6 µg/L), or a mixture of PPCPs consisting of atenolol (1.5 µg/L), caffeine (0.25 µg/L), diphenhydramine (0.1 µg/L), gemfibrozil (1.5 µg/L), ibuprofen (0.4 µg/L), naproxen (1.6 µg/L), triclosan (2.3 µg/L), progesterone (0.2 µg/L), triclocarban (1.4 µg/L), and DEET (0.6 µg/L). Quantitative real-time polymerase chain reaction revealed an upregulation in vitellogenin (vtg) in livers of females and males exposed to triclocarban. Also, an upregulation of hepatic lipoprotein lipase (lpl) and a downregulation of androgen receptor (ar) and steroidogenic acute regulatory protein (star) were observed in testes. The group treated with DEET only showed a significant decrease in ar in females. In contrast, the PPCP mixture downregulated vtg in females and males and expression of estrogen receptor alpha (erα), star, and thyroid hormone receptor alpha 1 (thra1) in testes. The authors' results show that the molecular estrogenic effects of triclocarban are eliminated (males) or reversed (females) when dosed in conjunction with several other PPCP, once again demonstrating that results from single exposures could be vastly different from those observed with mixtures. Environ Toxicol Chem 2014;33:910-919. © 2013 SETAC.

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Effects of gemfibrozil on lipid metabolism, steroidogenesis, and reproduction in the fathead minnow (Pimephales promelas)

Cited by 40 publications

References 48 publications

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

Effects of triclocarban, N,N‐diethyl‐meta‐toluamide, and a mixture of pharmaceuticals and personal care products on fathead minnows (Pimephales promelas)

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