First evidence that waterborne methylphenidate alters endocrine and behavioral stress responses in zebrafish

Endres, Helena Cristina; Rosa, João Gabriel da; Kalala, Celestin Kabasele; Barcellos, Heloísa Helena de Alcântara; Bertol, Charise Dallazem; Barcellos, Leonardo José Gil; Rossato‐Grando, Luciana Grazziotin

doi:10.1016/j.neulet.2017.04.039

Cited by 11 publications

(5 citation statements)

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“…The first step that we took to investigate the genetic signature of response to treatment was to assess the effect of MPH on a common behavioral trait, locomotor activity, and on gene expression in a WT mass population. We chose to investigate locomotor activity because: (1) altered activity patterns are a common characteristic of ADHD (American Psychiatric Association 2013; Faraone et al 2015); (2) administered MPH has known behavioral effects on locomotor activity in animal models such as D. melanogaster (van Swinderen and Flores 2006;van der Voet et al 2015), rats (Choi et al 2014;Dafny 2015), mice (Carmack et al 2014), and zebrafish (Nishimura et al 2015;Endres et al 2017); and (3) locomotor activity is quantifiable and well suited for high-throughput studies, and, in particular, video tracking assays have been successfully used previously to study abnormal behaviors in D. melanogaster (Pertoldi et al 2016;Rohde et al 2016bRohde et al , 2018. Jordan et al (2007) and Harbison et al (2013) also used inbred Drosophila lines (including the DGRP) to investigate the genetic architecture of behavioral traits, including sleep patterns and the startle response.…”

Section: Mph Alters Locomotor Activity and Gene Expression In A Wt Pomentioning

confidence: 99%

Genetic Signatures of Drug Response Variability inDrosophila melanogaster

et al. 2019

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Knowledge of the genetic basis underlying variation in response to environmental exposures or treatments is important in many research areas. For example, knowing the set of causal genetic variants for drug responses could revolutionize personalized medicine. We used Drosophila melanogaster to investigate the genetic signature underlying behavioral variability in response to methylphenidate (MPH), a drug used in the treatment of attention-deficit/hyperactivity disorder. We exposed a wild-type D. melanogaster population to MPH and a control treatment, and observed an increase in locomotor activity in MPH-exposed individuals. Whole-genome transcriptomic analyses revealed that the behavioral response to MPH was associated with abundant gene expression alterations. To confirm these patterns in a different genetic background and to further advance knowledge on the genetic signature of drug response variability, we used a system of inbred lines, the Drosophila Genetic Reference Panel (DGRP). Based on the DGRP, we showed that the behavioral response to MPH was strongly genotype-dependent. Using an integrative genomic approach, we incorporated known gene interactions into the genomic analyses of the DGRP, and identified putative candidate genes for variability in drug response. We successfully validated 71% of the investigated candidate genes by gene expression knockdown. Furthermore, we showed that MPH has cross-generational behavioral and transcriptomic effects. Our findings establish a foundation for understanding the genetic mechanisms driving genotype-specific responses to medical treatment, and highlight the opportunities that integrative genomic approaches have in optimizing medical treatment of complex diseases. KEYWORDS Ritalin; ADHD; Drosophila Genetic Reference Panel; cross-generational effects; locomotor activity U NDERSTANDING individual variability in response to treatment is one of the fundamental challenges in biological sciences. Treatment can be defined as any expected or unanticipated biotic or abiotic exposure; that is, any change in the environment of the organism, whether in the surrounding environment, such as temperature changes, or in the intrinsic environment, such as metabolic alterations caused by ingestion of chemicals. For many scientific fields-including medicine, animal and plant breeding, and evolutionary biology-knowledge of the mechanisms that underlie variability in how an individual responds to such treatment is important. This could, for example, involve predicting the consequences of climate change on species distribution, obtaining consistent output in livestock and plant breeding across heterogeneous production systems, or providing optimal treatment of conditions that require medical attention. The latter example was specifically investigated in the present study. Responses to pharmacological interventions are highly variable for many human diseases (Roden and George 2002). Personalized medicine has been proposed as a strategy to provide more accurate and effective medical treatm...

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Section: Mph Alters Locomotor Activity and Gene Expression In A Wt Pomentioning

confidence: 99%

Genetic Signatures of Drug Response Variability inDrosophila melanogaster

et al. 2019

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“…Methylphenidate and ritalinic acid have garnered recent research attention as surface water contaminants and a potential concern for aquatic wildlife (Letzel et al 2010 ; Endres et al 2017 ). To support future ecotoxicology studies on these compounds, we assessed the degradation of methylphenidate and formation of ritalinic acid in the water column and tissue uptake in two aquatic organisms at two temperatures.…”

Section: Discussionmentioning

confidence: 99%

“…Future ecotoxicological studies on methylphenidate using fish should carefully plan dosing and endpoint measurement considering compound degradation in the water column and rapid uptake in tissues. Studies to date, for example, Endres et al ( 2017 ) and De Serrano et al ( 2016 ), exposed fish for less than an hour and then measured physiological or behavioural endpoints. Our findings indicate that methylphenidate concentrations stay above ~ 180 ng/L (the concentration that Endres et al ( 2017 ) found increased on zebrafish cortisol) in the water column for up to 2 days.…”

Section: Discussionmentioning

confidence: 99%

“…Studies to date, for example, Endres et al ( 2017 ) and De Serrano et al ( 2016 ), exposed fish for less than an hour and then measured physiological or behavioural endpoints. Our findings indicate that methylphenidate concentrations stay above ~ 180 ng/L (the concentration that Endres et al ( 2017 ) found increased on zebrafish cortisol) in the water column for up to 2 days. It would be valuable to understand how methylphenidate affects fish physiology and behaviour over a longer (48 h) time-span.…”

Section: Discussionmentioning

confidence: 99%

“…Following a standard dose (18 mg), up to 80% is excreted as ritalinic acid (α-phenyl-2-piperidine acetic acid) that has little pharmacological activity (Faraj et al 1974 ; Concerta Prescribing Information 2013 ). Recently, Endres et al ( 2017 ) showed that exposure to environmentally relevant concentrations of methylphenidate reduced cortisol (i.e., stress) and inhibited anxiety-like behaviours (e.g., freezing, hiding) in stressed zebrafish ( Danio rerio ). Reductions in anxiety behaviours have been noted in adult guppies ( Poecilia reticulata ) exposed to 250 ng/L (De Serrano et al 2016 ) and in zebrafish exposed to a much higher concentration (50 mg/L) as embryos (Levin et al 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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Stability and uptake of methylphenidate and ritalinic acid in nine-spine stickleback (Pungitius pungitius) and water louse (Asellus aquaticus)

McCallum

Lindberg

Andersson

et al. 2019

Environ Sci Pollut Res

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The presence of human pharmaceuticals in the environment has garnered significant research attention because these compounds may exert therapeutic effects on exposed wildlife. Yet, for many compounds, there is still little research documenting their stability in the water column and uptake in organism tissues. Here, we measured the uptake and stability of methylphenidate (Ritalin®, a frequently prescribed central nervous system stimulant) and its primary metabolite, ritalinic acid, in (1) water only or (2) with nine-spine stickleback and water louse. Methylphenidate degraded to ritalinic acid in both studies faster at a higher temperature (20 °C versus 10 °C), with concentrations of ritalinic acid surpassing methylphenidate after 48–100 h, depending on temperature. The concentration of methylphenidate in stickleback was highest at the first sampling point (60 min), while the concentration in water louse tissues reached comparatively higher levels and peaked after ~ 6 days. Neither stickleback nor water louse took up ritalinic acid in tissues despite being present in the water column. Our findings provide valuable data for use in future risk assessment of methylphenidate and will aid in the design of studies aimed at measuring any ecotoxicological effects on, for example, the behaviour or physiology of aquatic organisms. Electronic supplementary material The online version of this article (10.1007/s11356-019-04557-9) contains supplementary material, which is available to authorized users.

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