Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children

Abstract

Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, −375, −423-5p, −30d-5p, −125b-5p, −4732-5p, −204-5p, and −574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, −940, −9-3p and −302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetylpara-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p<0.01) followed by miR-375 (R=0.70; p=0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

“…The control group ( n = 10; APAP dose = 0 mg/kg) consisted of healthy children without use of APAP in the preceding 14 days; APAP therapeutic group ( n = 10; APAP dose = 10.0–17.5 mg/kg) consisted of hospitalized children receiving APAP per standard of care; and APAP overdose group ( n = 8; APAP dose = 58.6–559.4 mg/kg) consisted of children requiring hospitalization for treatment of APAP overdose. The clinical and laboratory data of the subjects, including age, gender, APAP dose, ALT and APAP protein adducts, were reported in our former study (Yang et al 2015). …”

“…The relative mRNA levels for candidate genes were normalized to GAPDH levels, while cellular miRNA levels were normalized to U6 levels. The miRNA levels in serum samples were calculated by comparing to Let-7d levels, as described in our former reports (Yang et al 2015). The miRNA levels from cell culture medium for HepaRG cells after APAP treatment were adjusted by Spike-in control cel-miR-39, and compared to miRNA levels in the corresponding control samples.…”

“…miRNAs have been linked to liver injury and represent candidate biomarkers of liver injury because they are sufficiently stable in a wide range of biofluids, including serum (Baraniskin et al 2012; Chen et al 2008). Several studies have attempted to address the relationship of miR-NAs and APAP-induced hepatotoxicity (Krauskopf et al 2015; Vliegenthart et al 2015; Wang et al 2009; Ward et al 2014; Yang et al 2015). However, the fine regulatory mechanisms of these miRNAs in relation to APAP-induced hepatotoxicity are still unclear.…”

MicroRNAs Role in the Central Nervous System Development and Abnormalities

“…In the CNS, new roles of miRNAs in brain development and neurotoxicity have been just discovered. Although it is still difficult to clarify a cause/effect role of changes in miRNAs for the pathological conditions, application of miRNAs as biomarkers for neurological disorders and neurotoxic testing is promising [41,42].…”

Use of Circulating and Cellular miRNAs Expression in Forensic Sciences

“…Their studies reported a significant increase in plasma miRNAs such as miRNA-122, miR-NA-375, miRNA-423-5p, miRNA-30d-50, miRNA-125b-5p, miRNA-4732-5p, miRNA-204-5p, miRNA-574-3p, as well as urine miRNAs such as miRNA-375, miRNA-940, miR-NA-9-3p, and miRNA-302a. 36 Wang et al have studied the toxic effects induced by four volatile agents, formaldehyde, benzene, toluene, and xylene, on miRNA expression. Their studies underline significant changes in miRNA-1187, miRNA-125a-3p, miRNA-125b-5p, miRNA-466c-5p, miR-NA-5105, and miRNA-3472 expressions.…”