Abstract
The antidepressant fluoxetine (FLX), generally the first line of pharmacological treatment in adolescents and pregnant women with affective disorders, is an emerging endocrine disruptor that is also released to the environment through sewage. Recently, we demonstrated that FLX exposure during the first 6 days of life in zebrafish (ZF; Danio rerio) induced a male-specific reduction in the exploratory behavior in the adult ZF that was linked to a reduction in cortisol production that persisted across three generations. Here we investigated sex differences in the behavioral and stress responses following FLX (0.54 and 54 μg⋅L–1) exposure during two periods of sexual development in ZF; early (0–15 days post-fertilization, dpf) and late (15–42 dpf). Our findings revealed that the stress response in females was reduced compared to that of males independent of the treatment. We also found that FLX reduced total body cortisol levels in the adult ZF regardless of sex and window of exposure. The hypocortisol phenotype of our FLX-treated fish was associated with behavioral alterations in the adult fish, which depended on the window of exposure; males were more sensitive to FLX during early development whereas females were affected during late development. A sexually dimorphic behavioral response induced by the low cortisol phenotype was observed in the FLX-treated ZF; females had higher exploratory activity whereas the males had reduced behavior. In conclusion, FLX results in sex- and window of exposure-specific effects on the behavioral activities in adult ZF. These findings highlight the importance of sex differences and timing on the long-term effects of antidepressant treatments. Knowledge of the sex-specific effects of antidepressants and the importance of early life exposure to chemical stressors may help us understand the impact of highly prescribed drugs such as FLX on the fetus from FLX-treated pregnant women as well as aquatic species in environments receiving sewage effluents.
Highlights
Stress, including those caused by therapeutic drugs during sensitive periods of development, can permanently shape the adult neuroendocrine and behavioral responses to internal and external cues in humans, rodents, and teleost fish (Koehl et al, 2000; Bale et al, 2010; Pawluski et al, 2012; Wolstenholme et al, 2012, 2013; Aluru et al, 2017)
To determine if exposure to FLX during two different windows of sexual development induced a disruption of the stress axis similar to that observed in our previous study [27], we examined wholebody cortisol levels following an acute standardized net handling stressor in adult female and male ZF
Whole-body cortisol levels were significantly elevated by the acute stressor in the adult females (F1,34 = 110.153, P < 0.001) and males (F1,37 = 119.887, P < 0.001) from the CTR and FLX treatments following exposure period 1 (Figure 2A)
Summary
Stress, including those caused by therapeutic drugs during sensitive periods of development, can permanently shape the adult neuroendocrine and behavioral responses to internal and external cues in humans, rodents, and teleost fish (Koehl et al, 2000; Bale et al, 2010; Pawluski et al, 2012; Wolstenholme et al, 2012, 2013; Aluru et al, 2017). The early life exposure to FLX suppressed their adult stressinduced cortisol levels (Vera-Chang et al, 2018), the primary stress hormone in teleosts (Romero, 2004). This effect persisted for three consecutive generations in the unexposed descendants without diminution and was more pronounced in males (VeraChang et al, 2018). Prenatal and early postnatal FLX treatment decreased ambulation in the open–field test at postnatal day (PND) 40, an effect observed solely in males (Lisboa et al, 2007)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
