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Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12435-E12442. doi: 10.1073/pnas.1811695115. Epub 2018 Dec 10.

Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio.

Author information

1
Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
2
Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
3
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
4
Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
5
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada.
6
Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611.
7
Department of Physiological Sciences, University of Florida, Gainesville, FL 32611.
8
University of Florida Genetics Institute, University of Florida, Gainesville, FL 32611.
9
Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; trudeauv@uottawa.ca.

Abstract

The global prevalence of depression is high during childbearing. Due to the associated risks to the mother and baby, the selective serotonin reuptake inhibitor fluoxetine (FLX) is often the first line of treatment. Given that FLX readily crosses the placenta, a fetus may be susceptible to the disruptive effects of FLX during this highly plastic stage of development. Here, we demonstrate that a 6-day FLX exposure to a fetus-relevant concentration at a critical developmental stage suppresses cortisol levels in the adult zebrafish (F0). This effect persists for three consecutive generations in the unexposed descendants (F1 to F3) without diminution and is more pronounced in males. We also show that the in vivo cortisol response of the interrenal (fish "adrenal") to an i.p. injection of adrenocorticotropic hormone was also reduced in the males from the F0 and F3 FLX lineages. Transcriptomic profiling of the whole kidney containing the interrenal cells revealed that early FLX exposure significantly modified numerous pathways closely associated with cortisol synthesis in the male adults from the F0 and F3 generations. We also show that the low cortisol levels are linked to significantly reduced exploratory behaviors in adult males from the F0 to F2 FLX lineages. This may be a cause for concern given the high prescription rates of FLX to pregnant women and the potential long-term negative impacts on humans exposed to these therapeutic drugs.

KEYWORDS:

epigenetic; fluoxetine; stress; transgenerational; zebrafish

PMID:
30530669
PMCID:
PMC6310822
[Available on 2019-06-26]
DOI:
10.1073/pnas.1811695115

Conflict of interest statement

The authors declare no conflict of interest.

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