Early life exposure and microcystin toxicity: Effects on liver health and metabolic reprogramming

Evidence is strong for early childhood exposure effects individuals with physical , biological , chemical , or psychological stimuli. Results from American Academy of Pediatrics show that infants and children are at risk for early exposure to microcystin. Notably, infants and children are known to consume more water relative to their body weight when compared to adults and thus are at increased risk of water borne exposures to environmental contaminants. The present report tests the hypothesis that early childhood exposure to microcystin (MC), a PP2A inhibitor and a principal component of harmful algal blooms activate Kupffer cells and hepatic stellate cells, which are considered to be crucial mediators in hepatic fibrogenesis in an underlying condition of NAFLD. NAFLD is a hepatic manifestation of metabolic syndrome and it is widely perceived that western diet consumption has a distinct role in priming the liver towards metabolic reprogramming along with a second hit from environmental and genetic factors. Mice exposed to subchronic doses of microcystin-LR (MC-LR) for two weeks immediately after the end of weaning and with a parallel high fat diet co-exposure showed classical symptoms of early NAFLD linked inflammation. Cytokines and chemokines such as CD68, IL1β, MCP-1, and TNF-α, as well as α-SMA, hallmarks of NAFLD-linked inflammation were increased in the groups that were exposed to microcystin with high fat diet compared to the vehicle group. Also, NLRP3 KO mice showed significant decrease in the inflammation suggesting a decisive role of NLRP3 linked inflammasome activation and increased inflammation in these mice. The same trends were observed for liver injury biomarker IL-1β, indicating a worsening outcome in liver health. Clinically, serum alanine aminotransferase (ALT) levels were significantly higher in the group that was primed to Microcystin followed by high fat feeding when compared to controls. The results suggest that toddlers and children might be at a greater risk of microcystin exposure and subsequent liver damage since data generated in mice models are highly translatable to humans. The results also bode well to strong clinical data that suggest increased incidences of NAFLD and NASH cases in children and juveniles in the US and around the developed world.