Developmental exposure to acetaminophen does not induce hyperactivity in zebrafish larvae.
First line pain relief medication during pregnancy relies nearly entirely on the over-the-counter analgesic acetaminophen, which is generally considered safe to use during gestation. However, recent epidemiological studies suggest a risk of developing attention-deficit/hyperactivity disorder (ADHD)-like symptoms in children if mothers use acetaminophen during pregnancy. Currently, there are no experimental proofs that prenatal acetaminophen exposure causes developmental brain alterations of progeny. Exposure to high acetaminophen concentrations causes liver toxicity, which is well investigated in different model organisms. However, sub-liver-toxic concentrations have not been experimentally investigated with respect to ADHD endophenotypes such as hyperactivity. We used zebrafish to investigate the potential impact of acetaminophen exposure on locomotor activity levels, and compared it to the established zebrafish Latrophilin 3 (Lphn3) ADHD-model. We determined the sub-liver-toxic concentration of acetaminophen in zebrafish larvae and treated wild-type and lphn3.1 knockdown larvae with increasing concentrations of acetaminophen. We were able to confirm that lphn3.1 knockdown alone causes hyperactivity, strengthening the implication of Lphn3 dysfunction as an ADHD risk factor. Neither acute nor chronic exposure to acetaminophen at sub-liver-toxic concentrations in wild-type or lphn3.1 knock-downs increases locomotor activity levels. Together our findings show that embryonic to larval exposure to acetaminophen does not cause hyperactivity in zebrafish larvae. Furthermore, there are no additive and/or synergistic effects of acetaminophen exposure in a susceptible background induced by knock-down of lphn3.1. Our experimental study suggests that there is, at least in zebrafish larvae, no direct link between embryonic acetaminophen exposure and hyperactivity. Further work is necessary to clarify this issue in humans.
Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, 97074, Würzburg, Germany.|Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, ADHD Clinical Research Network, Laboratory of Translational Neuroscience, University of Würzburg, 97080, Würzburg, Germany.
Isabel
I
Reuter
Department of Human Genetics, Biocenter, Am Hubland, University of Würzburg, 97074, Würzburg, Germany.
Sabine
S
Knaup
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, 97080, Würzburg, Germany.
Marcel
M
Romanos
Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, ADHD Clinical Research Network, Laboratory of Translational Neuroscience, University of Würzburg, 97080, Würzburg, Germany.
Klaus-Peter
KP
Lesch
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, 97080, Würzburg, Germany. drepper_c@ukw.de.
Carsten
C
Drepper
Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, 97074, Würzburg, Germany. christina.lillesaar@biozentrum.uni-wuerzburg.de.
Christina
C
Lillesaar
D000082:Acetaminophen / Q000633:toxicity*; D000367:Age Factors; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000139:chemically induced* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007814:Larva / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
D018712:Analgesics, Non-Narcotic; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D018000:Receptors, Peptide; D000082:Acetaminophen
Acetaminophen; Behavior; Impulsivity; Locomotion; latrophilin3.1