Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafishDanio rerio

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.

Developmental fluoxetine exposure in zebrafish reduces offspring basal cortisol concentration via life stage-dependent maternal transmission

“…Serotonin, in this period, is considered an important regulator of motor neuron differentiation and locomotion in developing zebrafish [88,89], but whether developmental serotonin acts as a programmer of the endocrine stress axis in zebrafish has not been directly investigated. Irrespective of an involvement of developmental serotonin, a recent study [57] was first to show that developmental exposure to FLX (both exposed F 0 males and females) reduces F 0 baseline and mechanical stressor-induced whole-body cortisol levels, and that this phenotype can be transmitted in subsequent generations, especially in males. We here additionally determine that this developmental exposure to FLX in the F 0 generation results in maternal, but not paternal transmission of reduced basal cortisol to F 1 offspring generated from crosses of 5 months old, but not 9 months old F 0 zebrafish.…”

“…In both fish [20,36–38] and mammals [39,40] endocrine disrupting effects of FLX have been reported at and below human therapeutic plasma (equivalent) concentrations, which include the endocrine stress axis function [41–46]. While developmental [47–53] and adult [16,20,46,54–56] consequences of FLX exposure have been comparatively well studied in fish at different levels of biological organization [15], intergenerational effects of developmental FLX exposure have only recently been described in zebrafish [57]. This study revealed that developmental FLX exposure has the capacity to differentially reduce basal cortisol concentrations or blunt mechanical stressor induced cortisol concentrations in subsequent generations.…”

Social stress increases plasma cortisol and reduces forebrain cell proliferation in subordinate male zebrafish (Danio rerio)

“…Male zebrafish were randomly allocated to sham-treated and metyrapone-exposed groups that were held in static tanks (6 fish per tank). After an overnight acclimation period, the water in metyrapone-exposed tanks was replaced with 325.4 µmol l −1 metyrapone in system water (Vera-Chang et al, 2018). Water changes were carried out every 24 h and all tanks were covered to reduce degradation of metyrapone by light exposure.…”

The anti-lipidemic drug simvastatin modulates Epigenetic Biomarkers in the AmphipodGammarus locusta

“…In the last decade, a growing scientific interest on transgenerational epigenetic inheritance has emerged [69][70][71]. However, despite the increasing number of studies showing transgenerational epigenetic impacts, the integration of epigenetic markers in the frame of hazard and risk assessment is still not a reality.…”