The detrimental effects and mechanisms of Orlistat in disrupting energy homeostasis and reproduction in Daphnia magna

•ORL exposure inhibited lipase activity in D. magna.•ORL exposure downregulated reproductive capacity in D. magna.•ORL exposure disturbed energy homeostasis in D. magna.•Mitochondrial dysfunction occurred in D. magna after chronic ORL exposure.•D. magna boosted their glycolysis to counter energy deficiency. Orlistat (ORL) has been employed as an anti-obesity pharmaceutical for several decades. Given its low absorption rate, the majority of administered ORL is excreted into the environment with feces. It is crucial to collect scientific information regarding the possible ecological risks associated with ORL. Here, the effects of ORL on Daphnia magna were evaluated using a 21-day chronic test at concentrations of 1, 10, 100, and 1000 μg/L. We found the inhibition of feeding and swimming activities in the 100 and 1000 μg/L ORL exposed D. magna, respectively. Their digestive enzyme activities and metabolites were reduced even at 1 μg/L ORL exposure. It is noteworthy that exposure to 100 μg/L ORL induced a decrease in the reproductive capacity of D. magna, although no discernible genotoxicity was observed. To identify the toxicological mechanisms of ORL, a metabolic analysis was conducted on D. magna exposed to 1000 μg/L ORL. A comprehensive reduction in carbohydrates, lipids, and amino acids was observed, which resulted in a blockage of metabolic flux towards the TCA cycle, as evidenced by mitochondrial dysfunction. These findings substantiate the detrimental impact of ORL on D. magna and provide insights into the underlying molecular mechanisms from a metabolic perspective.