Abstract
Lymphoma is the most top 10 cancers in worldwide and the incidence rise strikingly since the last half of the 20th century. Lymphoma is a cancer affecting the immune system, the major risk factor is associated with exposure to occupational or environmental chemicals. Bisphenol A (BPA) is a common manufactory chemical widely used in polycarbonate and epoxy plastic products. BPA can alter gene expression to raise susceptibility of disease and cancer. BPA can interfere with immune reaction, and aberrant immune function has been reported that related to lymphoma incidence. BPA may be considered to induce lymphomagenesis through influencing immune system. However, the molecular effect of BPA exposure on lymphomagenesis has not been declared. Therefore, the purpose of this study was to investigate whether BPA exposure would lead to lymphomagenesis through gene dysregulation. This study conducted a meta-analysis in 309 microarray datasets of human NHL tissues and 98 microarray datasets of human cells in exposure to BPA. The differentially expressed genes (DEGs) of NHL and BPA exposure were identified individually. This study used weighted gene co-expression network analysis (WGCNA) to explore module genes of NHL and BPA exposure, respectively, and Cytoscape to construct the potential pathway of NHL progression in response to BPA exposure. The results of the gene-network analysis presented that BPA exposure could activate the CTNNB1 (catenin beta 1)-NFKB1 (nuclear factor kappa B subunit 1)-AR (androgen receptor)-IGF1 (insulin like growth factor 1)-TWIST1 (twist family BHLH transcription factor 1) pathway to lead to lymphomagenesis. Moreover, the result of gene-network analysis was validated in human lymphoblastoid TK6 cells. In TK6 cells, BPA exposure induced gene expression of CTNNB1, NFKB1, AR, IGF1 and TWIST1, caused DNA single strand and double strand damage, promoted G2/M cell cycle arrest, and reduced expression of DNA repair genes TP53 (tumor protein P53) and CDKN1A (cyclin-dependent kinase inhibitor 1A). This study demonstrated that transfection of siCTNNB1 attenuated BPA-induced NFKB1, AR, IGF1 and TWIST1 expression, diminished DNA damage and G2/M arrest, and elevated TP53 and CDKN1A expression for repair function. This study found that BPA exposure can cause DNA damage and disrupt cell cycle and DNA repair function potentially for lymphomagenesis underlying CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway.