Selective serotonin (5-HT) reuptake inhibitors (SSRIs) particularly fluoxetine (FLX, Prozac®), are often the first-line of pharmacological treatment for affective disorders in pregnant women. Given that SSRIs readily cross the placenta, a fetus from a SSRI-treated pregnant woman is potentially at risk from the disruptive effects of the SSRIs-induced 5-HT actions during this highly plastic stage of development. One of the prominent roles of 5-HT that we will explore here is its involvement in the development and programming of the stress axis. Pharmaceuticals including FLX and other SSRIs reach aquatic ecosystems through sewage release, so fish may also be inadvertently exposed. We investigated the premise that early-life exposure to FLX induces a transgenerational disruption of the stress axis using the zebrafish (ZF) Danio rerio, as a research model to encompass both the environmental and human health concerns. The FLX concentrations studied were environmentally relevant (0.54 µg·L-1) or comparable to concentrations detected in the cord blood of FLX-treated pregnant women (54 µg·L-1).
Exposure to FLX during the first 6 days of life induced a reduction of whole-body cortisol levels in adult ZF (filial generation 0; F0), an effect that persisted across 4 consecutive generations without diminution, even though the descendants (F1 to F4) were not directly exposed to FLX. This effect was more pronounced and persistent in males than females. The in vivo cortisol response of the interrenal cells (the fish ‘adrenal’) to an intraperitoneal injection of adrenocorticotropic hormone was also reduced in the F0 and F3 FLX-exposed males. RNA sequencing of the F0 and F3 male whole kidney containing the interrenal cells detected an array of differentially expressed genes (>500) altered by FLX treatment. Enrichment analysis of these genes revealed that early FLX exposure significantly modified numerous canonical pathways (>40) including key pathways related to steroidogenesis. These findings provide further insights on the underlying mechanism of the transgenerational disruption induced by FLX. We also showed that altered cortisol levels were linked to reduced exploratory behavior in adult males from the F0 to F2 FLX lineage. In contrast, females were susceptible to the effects of FLX-induced hypocortisolism during a different window of development. Exposure to FLX in the sex differentiation period (15 to 42 days post-fertilization) increased exploratory behavior in the adult females. Transcriptional profile of selected steroidogenic genes in the whole-larvae from the F0 varied in magnitude and direction in both treatments, despite the same low cortisol phenotype induced by both concentrations. We also found an up-regulation in the transcript levels of steroidogenic-related genes and a down-regulation of a gene involved in the inactivation of cortisol in the F3 larvae ancestrally exposed to the human-relevant concentration. These findings on the transcript levels of the selected genes in the larvae from F0 and F3 suggest that the larvae adopted specific coping mechanism(s) to the disruptive effects of FLX depending on the exposure concentration and the filial generation. The pigmentation patterns in some of the descendants of the exposed fish (F1 to F3) were reduced by the 6-day early-FLX treatment. In response to a 6-day embryonic exposure to a second antidepressant, venlafaxine, the F4 adult females that were ancestrally exposed (in the F0) to the human-relevant FLX concentration displayed an intensified reduction of cortisol levels. Therefore, FLX exposure of the great-great-grandparents (F0) permanently and most likely epigenetically shaped the response of future generations to other antidepressants. Collectively, our data are cause for concern, given the high-prescription rates of FLX to pregnant women and the potential long-term negative impacts on humans and aquatic organisms exposed to ever rising levels of SSRIs.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/38028 |
| Date | 24 August 2018 |
| Creators | Vera Chang, Marilyn Nohely |
| Contributors | Trudeau, Vance, Moon, Thomas |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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