Maternal Daphnia magna exposure to the antidepressant sertraline causes molting disorder, multi-generational reproductive and serotonergic dysfunction

Sertraline, one of the most commonly used antidepressants, has exhibited a progressively escalating trend in usage over the course of the last decades years, which have been exacerbated by the COVID-19 pandemic. Here, this study assessed the transgenerational effects of sertraline on the aquatic microcrustacean Daphnia magna, a parthenogenetic model species. The parental D. magna (G0) were exposed to environmentally relevant concentrations of sertraline (0.1 and 10 μg/L) for 21 days at individual and population level, and observed exposure triggered specific increased fecundity and desynchronized molting. These alterations were partially inherited through three subsequent non-exposed generations (G1, G2, and G3), as evidenced by increased fecundity and disordered molting in G1, reduced fecundity in G2, and reduced body size of G3-offspring. The molt-related genes neverland 1 and hormone receptor 3 were significantly different to the control group simultaneously only in the exposed generation, which may well be responsible for the molting asynchrony. Vitellogenin plays an important role in reproduction, and our results indicate that its abnormal expression persists up to G3, which was highly correlated with the expression of serotonin transporter, the drug target of sertraline. This finding suggested that sertraline possesses a sustained reproductive toxicity and disrupting potential and may be associated with serotonin dysregulation caused by compensatory feedback of serotonin transporter. In combination with male birth and upregulation of doublesex and vitellogenin, sertraline was deemed to trigger a self-defense response of D. magna, known as "abandon-ship" by increasing reproductive inputs. However, no males was found in individual reproduction test in each generation, which may suggest some interaction between sertraline and population density. Our findings emphasize that the toxic effects of sertraline can be transferred to unexposed generations, even with different adverse consequences, implying that future studies need to focus on transgenerational delayed effects and the underlying mechanisms.