Microcystin-RR is a biliary toxin selective for neonatal cholangiocytes

Abstract

BACKGROUND AND AIMSBiliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to be caused by a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an -methylene ketone group, was previously implicated in toxin-induced biliary atresia in Australian livestock, but is found in a limited location and is highly unlikely to be a significant human toxin. We hypothesized that other molecules with -methylene ketone groups, some with the potential for significant human exposure, might also be biliary toxins. APPROACH AND RESULTSWe focused on the family of microcystins, cyclic peptide toxins from blue-green algae that have an -methylene ketone group and are found worldwide, particularly during harmful algal blooms. We found that microcystin-RR, but not 6 other microcystins, caused damage to cell spheroids made using cholangiocytes isolated from 2-3-day-old mice, but not from adult mice. We also found that microcystin- RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice, but not 18-day-old mice. Microcystin-RR caused elevated reactive oxygen species in neonatal cholangiocytes, and treatment with N-acetyl cysteine partially prevented microcystin-RR- induced lumen closure, suggesting a role for redox homeostasis in its mechanism of action. CONCLUSIONSThis study highlights the potential for environmental toxins to cause neonatal biliary disease and identifies microcystin-RR acting via increased redox stress as a possible neonatal bile duct toxin.