Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio
- DOI
- Language of the publication
- English
- Date
- 2017-12-10
- Type
- Article
- Author(s)
- Vera-Chang, Marilyn N.
- St-Jacques, Antony D.
- Gagné, Rémi
- Trudeau, Vance L.
- Publisher
- National Academy of Sciences
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.
Plain language summary
Health Canada is responsible for the assessment and management of health risks to Canadians associated with exposure to pharmaceuticals, products and chemicals in the environment. The fetus is known to be particularly sensitive to risks posed by environmental chemicals and pharmaceuticals. The global prevalence of depression is high during childbearing. Fluoxetine (FLX) is often the first-line of treatment for depression and is present in the waste water effluent of sewage treatment plants. Given that FLX readily crosses the placenta, a fetus may be susceptible to the disruptive effects of FLX. Researchers from the University of Ottawa and Health Canada collaborated in this study to demonstrate that a 6-day FLX exposure to a fetus-relevant concentration at a critical developmental stage suppresses cortisol (the body’s main stress hormone) levels in the adult zebrafish (F0). This effect persisted for 3 consecutive generations in the unexposed descendants (F1 to F3) without diminution and was more pronounced in males. Analysis of gene expression changes in adrenal cells found in the kidney of the zebrafish revealed that early FLX exposure significantly modified numerous biological pathways closely associated with cortisol synthesis in the male adults from the F0 and F3 generations. The low cortisol levels were also linked to significantly reduced exploratory behaviors in adult males from the F0 to F2 FLX lineages. This research demonstrates that additional work is needed to explore the relevance of these findings to humans. The research will be used to inform the design of future experiments to establish the causes of these effects, its relevance to humans, and additional exposures that may cause similar effects. Overall, these results will be used to better refine approaches to characterize the human health risks from environmental exposures.
Subject
- Health,
- Health and safety