Metabolic and Reproductive Effects of Relatively Low Concentrations of Beclomethasone Dipropionate, a Synthetic Glucocorticoid, on Fathead Minnows

Pharmaceuticals present in the aquatic environment could adversely affect aquatic organisms. Synthetic glucocorticoids (GC) are used in large quantities as anti-inflammatory drugs and have been reported to be present in river water. In order to assess the impact of environmental concentrations of GCs, an in vivo experiment was conducted with adult fathead minnows. Fish were exposed to 0.1 μg/L, 1 μg/L, or 10 μg/L beclomethasone dipropionate (BCMD) via a flow-through system over a period of 21 days. Similar duplicate tanks served as control, with no chemical added. There was a concentration-related increase in plasma glucose concentration and a decrease in blood lymphocyte count. Induction of male secondary sexual characters and a decreasing trend in plasma vitellogenin (Vtg) concentrations in female fish were observed with increasing exposure concentration of BCMD. Expression profiles of selected genes (phosphoenolpyruvate carboxykinase - PEPCK, glucocorticoid receptor - GR, and Vtg) in liver also demonstrated concentration-related effects at all three tested concentrations. The results suggest that GCs could cause effects in lower micrograms per liter concentrations that could be environmentally relevant for total GCs present in the environment. Therefore, studies to determine the environmental concentrations of GCs and no effect concentrations are needed to assess if GCs pose a risk to the aquatic environment

The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals

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

Effects of fluoxetine on fish - Dataset - Margiotta-Casaluci et al. 2014

The file provides the results of a study during which male fathead minnows were exposed for 28 days to the anti-depressant fluoxetine

Relationship between plasma concentrations of norfluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.

<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 72–258 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p

Inter-individual and intra-treatment variability of fluoxetine plasma concentrations.

<p>The unit of the values indicated in the columns Mean, Median, Min, Max, 25%, and 75% is ng/mL.</p><p>Inter-individual and intra-treatment variability of fluoxetine plasma concentrations.</p

Relationship between plasma concentrations of fluoxetine plus norfluoxetine and their effects on fish exploratory behaviour after 28 days of exposure.

<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine + norfluoxetine plotted in the graphs is 163–560 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p

Relationship between plasma concentrations of fluoxetine and behavioural endpoints expressed as median values.

<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test after 28 days of exposure. The dose-response of behavioural endpoints appears to be visually more obvious when median values are used (in this figure) instead of mean values (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110467#pone-0110467-g004" target="_blank">Figure 4</a>). This highlights the important role of inter-individual variability in the interpretation of behavioural effects. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as medians (<i>n</i> = 20). *: <i>p</i><0.05.</p

Effect of fluoxetine on fish exploratory behaviour quantified during a Novel Tank Diving Test performed after 14 days of exposure.

<p>A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area. C1 and C2 indicate control group 1 and control group 2, respectively. Boxes represent medians (full line), with 5th and 95th percentiles (<i>n</i> = 20). *<i>p</i><0.05.</p

Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.

<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p

Methodological procedure for the quantification of fish behaviour.

<p>A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) <i>versus</i> active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).</p