Low doses and lifecycle exposure of waterborne antidepressants in zebrafish model: A survey on sperm traits, reproductive behaviours, and transcriptome responses.

Venlafaxine and citalopram have been commonly found in surface water and may disrupt fish reproduction, yet the long-term impact and the underlying mechanism are largely unknown. Here, zebrafish were exposed to 0.1-100 μg/L venlafaxine and citalopram for their entire life cycle from embryo to adult, respectively. After exposure for 180 days, the lowest observable effective concentration (LOEC) of venlafaxine and citalopram to significantly reduce the mean number of egg production in adults were 10 and 1 μg/L, respectively, whereas the fertilization rate displayed no significant changes. Further, we investigated the impacts of venlafaxine and citalopram in a reproductive context, including sperm quality and reproductive behaviour. In contrast, venlafaxine and citalopram exposure did not affect sperm quality but caused a reduction of reproductive behaviour (e.g., mating duration and mating interval) of adults exposed to 1-10 μg/L of the antidepressant. Transcriptomic profiling of the whole ovary revealed that lifecycle venlafaxine and citalopram exposure significantly affected the Na/Cl dependent neurotransmitter transporters signaling. Moreover, immune system-mediated ovarian regeneration and creatine metabolism regulated energy metabolism were proposed as the novel mechanism in the observed effects. Taken together, our results highlight the risk of lifecycle venlafaxine and citalopram exposure to fish reproduction and provide novel perspectives for unveiling the mechanism of female reproductive dysfunction.