Aquatic Toxicology 146 (2014) 261–263

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Commentary

Response to Commentary on “Are some invertebrates exquisitely sensitive to the human pharmaceutical fluoxetine?” C. Di Poi, C. Bellanger ∗ Normandie Université, GMPc, EA 4259, F-14032 Caen cedex, France

We appreciate the commentary made by Sumpter and Margiotta-Casaluci (in this issue) who are participating in the brainstorming around the effects of antidepressants on non-target aquatic organisms based on two recent articles published in Aquatic Toxicology, our paper Di Poi et al. (2013) and Franzellitti’s article (Franzellitti et al., 2013). 1. What do we know on the contamination level of marine waters? Sumpter and Margiotta-Casaluci firstly highlight the scarcity of the data available regarding the contamination levels by antidepressants, let’s say more broadly “psychotropic drugs”, in marine waters. To our knowledge, there are only two publications reporting the concentrations of several psychotropic drugs in French coastal waters (Togola and Budzinski, 2008; Munaron et al., 2012). One paper shows that the levels of the antidepressant amitriptyline and the anxiolytics, diazepam and nordiazepam, reached 10 ng/L in seawater samples collected along the Mediterranean coastline (Togola and Budzinski, 2008). In addition, a large-scale study using polar organic contaminant integrative samplers (POCIS) shows that the levels of diazepam and nordiazepam quantified at different sampling sites within the same area reached 1–4 ng/g of sorbent (Munaron et al., 2012). 2. Is the read-across hypothesis valid for cephalopods? The Read-Across hypothesis discussed in the commentary, and more deeply reviewed in Rand-Weaver et al. (2013), states that a drug will have an effect in non-target organisms if the molecular targets, usually a receptor or an enzyme, have been conserved throughout evolution resulting in a specific effect when plasma concentrations are close to therapeutic concentrations in human, e.g., 50–500 ␮g/L for fluoxetine. Cephalopods are not yet supported by this hypothesis. The complexity of their behavioral repertoire, their cognitive abilities, and the functional anatomy of their “brain” are well studied (see for a review, Hanlon and Messenger, 1996; Dickel et al., 2013). But there is little information available on

∗ Corresponding author. E-mail address: [email protected] (C. Bellanger). 0166-445X/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.aquatox.2013.11.020

the localization, the structural and functional features of biogenic amines and on the presence of their receptors in their nervous system. As suggested by the authors, the measurement of the fluoxetine concentrations in the total hemolymph (or in the plasma) of invertebrate species could be an alternative to know whether the molecule has been taken up by the organism. It would allow us to estimate the blood/plasma concentrations at which the effects of the antidepressant occur. This is tricky challenging in most of invertebrates that possess an open circulatory system; although cephalopods have a well developed, semi-closed system of hemolymph circulation. However, the hemolymph, and more specifically hemocyctes and plasma (cell-free hemolymph), of bivalve molluscs remain attractive for assessing biomarker responses to environmental stressors such as chemical contamination by metals (e.g., Al-Subiai et al., 2009) and organic pollutants (Rickwood and Galloway, 2004). Published data are not yet available regarding the contamination of hemolymph by antidepressants, and even more widely on pharmaceuticals in any invertebrate species. On the other hand, toxic effects driven by non-specific mechanisms are also possible in non-target species due to the penetration of the antidepressant into cells when pharmacological targets are not present. For example, Rainey et al. (2010) demonstrate that many psychoactive cationic amphiphiles, such as sertraline, target phospholipid membranes in the yeast strain Saccharomyces cerevisiae. El-Bassat et al. (2011) show that 72-h exposure to fluoxetine causes cell rupture and cell deformations at low concentrations (30–50 ␮g/L) in algae and in several zooplankton species. Cleuvers (2003) reports that two anti-inflammatory drugs, diclofenac and ibuprofen, act unspecifically by non-polar narcosis in Daphnia Daphnia magna, in the chlorophyte Desmodesmus subspicatus and in the duckweed Lemna minor. This author suggests that their toxicity may be associated with the log Kow (octanol-water partition coefficient) of the drugs rather than any specific action. 3. Effects observed on learning and memory at low concentration, isn’t that surprising! The authors comment that in our study the effects of fluoxetine on cognitive abilities were observed at the low concentration of 1 ng/L, that is under the concentrations at which effects occurred

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in other aquatic invertebrates (e.g., Bringolf et al., 2010; Guler and Ford, 2010; Lazzara et al., 2012; Fong and Molnar, 2013). Interspecific comparisons are very difficult, even impossible. All the effects reported could be age-dependent, species-dependent even within the same phylum (Mollusca), and also dependent on the experimental design (e.g., mode and duration of exposure, etc.). Hence, the severity of the effects observed for one molecule is likely also dependent on the endpoint we monitor. In our study, we focused on one of the most sophisticated molluscs, the cuttlefish, which exhibits a highly developed and centralized nervous system much closer to that of vertebrates than to any other invertebrate species (Dickel et al., 2013). In addition, we tested young cuttlefish at the age of 1-month following a long-term exposure to fluoxetine, from 15-day pre-hatching to 30-day post-hatching. The perinatal period is likely the most critical period in the cuttlefish’s life during which intense brain processes occur (reviewed in Dickel et al., 2013). The brain is likely a highly sensitive organ to a xenobiotic exposure at this time. Serotonin (5-HT) is present in large quantities in cephalopods’ nervous system. In cuttlefish, 5-HT immunoreactivities have been widely detected in a brain region (Boyer et al., 2007), the vertical complex which is implicated in learning and memory processes (Shomrat et al., 2010). The Selective Serotonin Reuptake Inhibitor (SSRI) fluoxetine targets the 5-HT system in the brain by specifically blocking serotonin reuptake transporters. Owing to the early presence of 5-HT neurons in the brain of several coleoid cephalopod species during ontogeny (e.g., in the pygmy squid, Wollesen et al., 2010; in octopods, Wollesen et al., 2012), fluoxetine could have an action on the maturation of key brain structures in the developing cuttlefish. Recent data show that fluoxetine exposures during embryonic development significantly decreased cell proliferation in the vertical and left optic lobes at 1 ␮g/L in newly hatched cuttlefish, and this may consequently affect brain maturation (Bidel et al., 2013 poster presentation). This cell proliferation decrease in vertical lobe may underlie the impairment of cognitive abilities observed in our study (Di Poi et al., 2013). Moreover some pharmaceuticals, such as fluoxetine, can bioconcentrate in organisms resulting in an internal concentration several fold higher than the surrounding water concentration (e.g., in fish tissues; Brooks et al., 2005). In our study, cuttlefish were exposed about 45 days at 1 and 100 ng/L of fluoxetine in water. This might have been led to high amounts of the drug inside the organisms and ultimately drive to cognitive, and likely behavioral, modifications even at low concentrations. It is also possible that the effects reported after 45 days of exposure would not have been observable if animals had been previously exposed on a shorter period of time. In order to answer this question, dosages in cuttlefish tissues sampled at different ages and at different time of exposure are in progress and will tell us the amount of the drug actually taken up by the animals when effects are obvious.

4. The use of cephalopods for scientific purposes are regulated The authors emphasize that we provided results from only one experiment. We agree that additional experiments must be conducted in order to confirm the reliability of the effects of fluoxetine we observed on learning and memory abilities. In ecotoxicological studies, there is a common principle to replicate the number of animals tested per concentration within one experiment and to repeat the experiment with several other batches of animals in order to confirm the consistency of the measure. However, when studying high-evolved species such as the cuttlefish, it raises an ethical concern. Nowadays, animal welfare concerns led to include cephalopods in a European Directive on animal protection (Directive on the protection of animals used for scientific purposes:

Directive 2010/63/EU) and in a French Legislation for animal experimentation (Décret n◦ 2013-118 of February 1st, 2013). In conclusions, our study (Di Poi et al., 2013) participates in filling knowledge gaps on pharmaceutical ecotoxicity in non-target marine species. Cephalopods are among the most fascinating and sophisticated invertebrates populating our oceans. There are about 700 living species on our planet and their biomass is considerable. Moreover, they have a fairly worldwide distribution inhabiting more or less polluted seas and oceans (Boyle, 1983). Cephalopods are very sensitive to marine pollution, such as heavy metals (e.g., Bustamante et al., 2004), and therefore appear to be very important organisms to consider for the assessment of the contamination level of the oceans. Hence they are reliable organisms in ecotoxicology when studying behavioral endpoints, but they make difficult the interpretation of the mechanisms underlying the effects of bioactive contaminants because the neurobiology of their brain fails to be fully understood.

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Response to commentary on "are some invertebrates exquisitely sensitive to the human pharmaceutical fluoxetine?".

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