Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review

As a ubiquitous environmental pollutant, benzo[a]pyrene (BaP) has been extensively studied for over 80 years. While much research has focused on its genotoxic and carcinogenic effects, considerably less attention has been paid to the osteotoxicity of BaP. Notably, environmental exposure to BaP is associated with skeletal malformation and bone impairment. Recent studies indicated that ancestral BaP exposure can cause transgenerational osteotoxicity in the unexposed F3 offspring. The consequences of environmental BaP/PAH pollution are thus likely to be severe and require re-assessment. We have reviewed the research status of BaP osteotoxicity, and a summary of genetic and epigenetic factors in the regulation of bone metabolism is provided as the basis for elucidating the mechanisms underlying transgenerational BaP osteotoxicity. Based on published studies on this topic, we propose that the transgenerational inheritance of osteotoxicity in fish induced by ancestral BaP exposure is mediated via epigenetically dysregulated bone miRNAs/genes. Two possible epigenetic regulatory circuits of BaP on bone miRNAs and genes are proposed: (i) bone miRNAs are dysregulated via altered DNA methylation and/or histone modifications, affecting target gene expression/activity; (ii) dysregulation of bone genes through altered DNA methylation and/or histone modifications. Our proposed mode of action (MOA) intends to serve as a basis for hypothesis testing in further in-depth studies. We emphasize that future works must verify the proposed MOA to assess its human relevance, and to decipher the underlying mechanism(s) of transgenerational BaP osteotoxicity.