Sex-Specific and Long-Term Impacts of Early-Life Venlafaxine Exposure in Zebrafish

SIMPLE SUMMARY: Excessive use of antidepressants, combined with our inability to completely clear them from municipal wastewater effluents, has led to their increased presence in aquatic habitats. Venlafaxine, one of the more commonly prescribed antidepressants, has been shown to be detrimental to the early life stages of non-target animals such as fish. Exposure to venlafaxine at the embryonic stage appears to lead to behavioural disruptions when zebrafish become free swimming and reduces growth in juveniles. Here we tested whether early-life exposure also led to behavioural and metabolic perturbations in adults using zebrafish, a widely utilized model in developmental toxicology. Zygotic exposure to venlafaxine compromised activity and anxiety responses and reduced the active metabolic rate as well as the aerobic scope in a sex-specific manner. This study raises the possibility that early developmental exposure to venlafaxine may have long-term consequences on fish performance, and that this may be sex dependent. ABSTRACT: Venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is a widely prescribed antidepressant that is detected in municipal wastewater effluents at µg/L concentrations. It has been shown to impact the early life stages of fish, including neurodevelopment and behaviour in larvae, but whether such early exposures have longer-term consequences are far from clear. Here, we sought to determine whether zygotic deposition of venlafaxine, mimicking a maternal transfer scenario, disturbs the metabolic rate and behavioural performance using zebrafish (Danio rerio). This was tested using freshly fertilized embryos (1–4 cell stage) microinjected with either 0, 1 or 10 ng of venlafaxine and raised to either juvenile (60 days post-fertilization) or adult (10–12 months post-fertilization). Zygotic venlafaxine exposure led to a reduction in the active metabolic rate and aerobic scope, but this was only observed in female fish. On the other hand, the total distance travelled in an open field assessment was greater at the highest concentration of venlafaxine only in the adult males. At the juvenile stage, behavioural assessments demonstrated that venlafaxine exposure may increase boldness—including hyperactivity, lower thigmotaxis, and a reduction in the distance to a novel object. Taken together, these results demonstrate that zygotic venlafaxine exposure may impact developmental programming in a sex-specific manner in fish.