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Edited by Bruce McEwen, The Rockefeller University, New York, NY, and approved November 8, 2018 (received for review July 17, 2018)
Significance
Due to the high incidence of depression during childbearing, antidepressants such as fluoxetine (FLX) are highly prescribed during pregnancy, yet the risks to offspring are unknown. We report that a 6-day FLX exposure during early zebrafish development induces hypocortisolism for at least three generations. Gene expression analysis indicates that pathways controlling cortisol synthesis are altered in the descendants in the third generation. This FLX-induced low-cortisol phenotype is more prominent in males and is associated with significantly reduced exploratory behaviors for two generations. This is an important demonstration that, in an animal model, even a brief ancestral exposure to a common antidepressant modifies the stress response and critical coping behaviors for several generations.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: trudeauv{at}uottawa.ca.
Author contributions: M.N.V.-C., T.W.M., and V.L.T. designed research; M.N.V.-C. performed research; A.D.S.-J., R.G., C.J.M., C.L.Y., T.W.M., and V.L.T. contributed new reagents/analytic tools; M.N.V.-C., A.D.S.-J., and R.G. analyzed data; and M.N.V.-C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo/ (BioProject ID PRJNA481502).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1811695115/-/DCSupplemental.
Published under the PNAS license.
References
Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio
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