Zygotic exposure to venlafaxine disrupts cortisol stress axis activity in multiple generations of zebrafish

Ubiquitous use of antidepressants has resulted in increased concentrations of these pharmaceuticals in waterways receiving municipal wastewater effluent. Amongst these, venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly found at concentrations surpassing 1 ppb in surface waters. We recently showed that the deposition of venlafaxine in zebrafish (Danio rerio) embryos impacts neural development in the hypothalamus, suggesting the possibility of neuroendocrine disruptions due to this antidepressant. Here, we tested the hypothesis that early developmental exposure to venlafaxine disrupts the long-term functioning of the hypothalamus-pituitary-interrenal (HPI) axis in zebrafish. Embryos (1-4 cell stage) were injected with either 0, 1, or 10 ng venlafaxine, and the ontogeny of cortisol content, as well as changes in cortisol levels following a stressor in larvae and adults were assessed across 3 generations. Zygotic venlafaxine exposure did not affect the ontogeny of cortisol production, but there was a disruption in the cortisol response to stressor exposure, which was also evident in multiple generations. In the F₀ generation, venlafaxine exposure did not affect cortisol levels in response to stressor exposure in larvae, but adult females, and not males, showed an attenuated cortisol response compared to control fish. This reduction in cortisol levels in the females was rescued by stimulation with adrenocorticotropic hormone, suggesting that the disruption was at the level of the hypothalamus-pituitary axis. Venlafaxine-mediated disruption in HPI axis functioning was also evident in the F₁ and F₂ generations, including impaired cortisol responses to a stressor in adult female and larval fish, respectively. Taken together, our results suggest that venlafaxine is an endocrine disruptor, and early developmental exposure to this antidepressant may have long-term and generational consequences on cortisol stress axis activity in zebrafish.