Epigenomic mechanisms are involved in PCB disruption: effects of a prenatal treatment on epigenomic hallmarks in rat liver

Introduction: The environment of early life has an important impact on health trajectories during the life, generating vulnerabilities to chronic disease. Epigenome is an important target of environment, modulating disease susceptibility during the whole life. Epigenetic represents the programming of the genome to express the appropriate set of genes in specific cells at specific time points in life. Since epigenetic mechanisms are established early in life, the developmental period represents a phase of maximal sensitivity to environmental influence The two main epigenetic controls are: 1- the methylation status of cytosines within CpG islands located in the promoter region of many genes; 2- post-translational acetylation or methylation of lysines in the histone N-terminal region, which influence chromatin packaging. Deregulation of epigenetic mechanisms may be responsible for faulty transcription patterns during critical periods of development, resulting in stable modifications of many key physiological processes. Prenatal exposure to PCBs (polychlorinated biphenyls), an important class of endocrine disruptors, through placental transfer and lactation, modifies the transcription pattern of many proteins, including steroid receptor and enzymes involved in sex steroid metabolism; furthermore it is known that steroid receptor could act also as co-regulator of histone modifications enzymes. It is unclear whether the action of PCBs is mediated only through receptor-mediated mechanisms or whether alterations of the epigenetic mechanisms are also involved. Aim: to evaluate whether prenatal administration of four PCB indicators (138, 153, 180, 126) is able to influence the epigenetic signature in liver of exposed animals. Results: PCB exposure reduces the lysine 4 trimethylation on histone 3 (H3K4me3) and the lysine 16 acetylation on histone 4 (H4K16Ac) (hallmarks of transcription activation) in a dimorphic way, probably producing a generalized inhibition of gene transcription. Moreover expression of histone modification enzymes, Jarid1b (gene and protein expression) and SirtT1 (gene expression), has been induced according to reduction of H3K4me3 and H4K16Ac in a dimorphic way. Interestingly gene and protein expression of androgen receptor has been reduced, especially in females. ChIP performed against H3K4me3 doesn’t show any correlation between AR promoter and presence of H3K4me3. Conclusion: exposure to PCBs might interfere with many developmental processes through epigenetic alterations of chromatin packaging in a dimorphic way, probably through an impaired interaction between androgen receptor and modification post-translational enzymes.