Intracranial Hemorrhage in Zebrafish: An Adverse Outcome Induced by Lovastatin

Abstract

Statins are one of the most commonly prescribed medications in the world, used in the treatment of hypercholesterolemia, and consequently, statin residues in aquatic environments can pose a potential risk to nontarget organisms. Here, we show that lovastatin causes a significant increase of intracranial hemorrhage (ICH, ∼60% at 1 μg/L) and subsequent chronic lethality (>70% at 1 μg/L) at low concentrations (0.5–1 μg/L) in larval zebrafish. Over 50% of the ICH larvae recovered late in development, yet serious cerebrovascular injury (decreased total vessel length, number of junctions, and end points) and locomotive inhibition persisted. Transcriptional responses indicated significant alterations in tight junctions, neurotrophic, and pro-inflammatory factors. Notably, intervention to restore prenylation but not cholesterol biosynthesis almost completely blocks the occurrence of ICH, with larvae survival rates reaching 60%. Thus, our results show that lipid-regulating agents in aquatic environments can weaken fish cerebrovascular systems and cause chronic lethality that should not be overlooked.