Abstract
Fluoxetine (FLX) is a pharmaceutical used to treat affective disorders in humans, but as environmental contaminant also affects inadvertently exposed fish in urban watersheds. In humans and fish, acute FLX treatment and exposure are linked to endocrine disruption, including effects on the reproductive and stress axes. Using the zebrafish model, we build on the recent finding that developmental FLX exposure reduced cortisol production across generations, to determine possible parental and/or life-stage-dependent (age and/or breeding experience) contributions to this phenotype. Specifically, we combined control and developmentally FLX-exposed animals of both sexes (F0) into four distinct breeding groups mated at 5 and 9 months, and measured offspring (F1) basal cortisol at 12 dpf. Basal cortisol was lower in F1 descended from developmentally FLX-exposed F0 females bred at 5, but not 9 months, revealing a maternal, life-stage dependent effect. To investigate potential molecular contributions to this phenotype, we profiled maternally deposited transcripts involved in endocrine stress axis development and regulation, epigenetic (de novo DNA methyltransferases) and post-transcriptional (miRNA pathway components and specific miRNAs) regulation of gene expression in unfertilized eggs. Maternal FLX exposure resulted in decreased transcript abundance of glucocorticoid receptor, dnmt3 paralogues and miRNA pathway components in eggs collected at 5 months, and increased transcript abundance of miRNA pathway components at 9 months. Specific miRNAs predicted to target stress axis transcripts decreased (miR-740) or increased (miR-26, miR-30d, miR-92a, miR-103) in eggs collected from FLX females at 5 months. Increased abundance of miRNA-30d and miRNA-92a persisted in eggs collected from FLX females at 9 months. Clustering and principal component analyses of egg transcript profiles separated eggs collected from FLX-females at 5 months from other groups, suggesting that oocyte molecular signatures, and miRNAs in particular, may serve as predictive tools for the offspring phenotype of reduced basal cortisol in response to maternal FLX exposure.
Highlights
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed pharmaceuticals used to treat mood disorders [1]
With regard to the glucocorticoid receptor gr (Fig 3A), we found a reduction in transcript abundance in eggs collected from 5 months old females which were developmentally exposed to FLX (F = 20.102, p = 0.001), but not in eggs collected from FLX females at 9 months
With regard to stress axis transcripts, we identified a significant reduction of gr and an induction of pomcb in FLX-group eggs collected at 5 mpf compared to controls, and a reduction of fkpb5 in eggs collected in the FLX group compared to the control group at 9 mpf
Summary
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed pharmaceuticals used to treat mood disorders [1]. Prescriptions of SSRIs have doubled in the past decades in many countries, reaching prescription rates as high as 10–15% of the adult population, with up to 2-fold higher prescription rates in women [2,3,4,5,6]. This raises concerns about potential effects of perinatal SSRI exposure in the offspring [7], as in pregnant or nursing women, prescription rates of 1–10% have been reported [8,9]. In fish [20], as in mammals [21], one of several roles of serotonin is the regulation of the endocrine system, including the stress axis [22,23]
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