A meta-analysis of randomized controlled studies on the hepatoxicity induced by polybrominated diphenyl ethers (PBDEs) in rats and mice

Abstract

Several toxicological studies were conducted to evaluate the hepatoxicity of PBDEs using different animal models, congeners, duration of exposure, and other parameters. These variations in different animal models and conditions might have an impact on extrapolating experimental results to humans. Hence, by the meta-analysis, we aimed to clarify and elucidate the species differences in hepatoxicity induced by PBDE exposure in rats and mice across different conditions and moderators. Fourteen in vivo studies that utilized rats and mice models were identified, and data such as author names, year of publication, type of PBDE congeners, rodent species, life stage of exposure, dosage, duration, and hepatoxicity indicators were extracted. The pooled standard mean difference (SMD) with a 95% confidence interval (95% CI) was used to evaluate the association between hepatoxicity and PBDE exposure across multiple approaches of measurement. Subgroup analysis, meta-regression, and interaction analysis were utilized to elucidate the species-related differences among the results of the involved studies. The pooled SMD of hepatoxicity of PBDE exposure in the involved in vivo studies was 1.82 (p = 0.016), indicating exposure to PBDE congeners and mixtures is associated with a significant increase in liver toxicity in rodents. Moreover, findings showed that rats were more sensitive to PBDEs than mice with the BDE-209 had the highest SMD value. Among the life stages of exposure, embryonic stage was found to be the most sensitive to hepatoxicity induced by PBDE congeners. Positive relationships were found between the incidence of hepatoxicity with dosage and duration of exposure to PBDE. Interaction analyses showed significant interactions between rodent species (rats or mice), dosage, length of exposure, and hepatotoxicity endpoints. Rats demonstrated an increased susceptibility to variations in organ weight, histopathological changes, mitochondrial dysfunction, and oxidative stress markers. Conversely, mice showed pronounced lipid accumulation and modifications in liver enzyme expression levels. However, significant differences were not found in terms of endoplasmic reticular stress as a mechanistic endpoint for hepatotoxicity. In conclusion, this meta-analysis showed that there might be some species-related differences in hepatoxicity induced by PBDE exposure in rats and mice depending on the parameters used. This study highlights the importance of cross-species extrapolation of results from animal models to accurately assess the potential risks to human health from exposure to PBDEs.