Editor’s Highlight: Interactive Genotoxicity Induced by Environmentally Relevant Concentrations of Benzo(a)Pyrene Metabolites and Arsenite in Mouse Thymus Cells

Abstract

Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As þ3 ) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As þ3 and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As þ3 induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As þ3 and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As þ 3 þ 100 nM BP-diol and 50 nM As þ 3 þ 100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4-dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As þ3 and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/ CYP1B1 may act together to increase DNA damage produced by As þ3 and PAHs.

Assessment of arsenic and polycyclic aromatic hydrocarbon (PAH) exposures on immune function among males in Bangladesh

“…A formal statistical test of PAH-DNA adducts and UAs/Cr levels showed no interactions between these two exposures. This was somewhat surprising because we have previously shown in mice a PAH and arsenic interaction in vitro [17, 45] and in in vivo . However, these studies were performed using mouse peripheral lymphoid tissues (spleen and thymus).…”

“…We cannot assume that the findings would be comparable in human blood cells. In addition, the clearest indication of synergistic interactions between PAHs and arsenic was in mouse thymus in vivo and in vitro studies, whereas we examined DNA damage and PARP inhibition [45]. Genotoxicity has been associated with cancer induced by arsenic and PAHs [46].…”

Arsenic exposure associated T cell proliferation, smoking, and vitamin D in Bangladeshi men and women

“…The consequences of immunosuppression produced by arsenic include an increased susceptibility to infections [3,24,26,27]. The genotoxic actions of arsenic are likely due to increased DNA damage and oxidative stress [21,[28][29][30][31][32]. The non-genotoxic actions of arsenic are associated with altered signaling pathways [33,34].…”

PAHs Target Hematopoietic Linages in Bone Marrow through Cyp1b1 Primarily in Mesenchymal Stromal Cells but Not AhR: A Reconstituted In Vitro Model

“…Animals were treated with PAH, TCDD, or vehicle control (olive oil) via a single IP injection (DMBA, 50 mg/kg; BP, 50 mg/kg; TCDD, 0.03 mg/kg (Accustandard; New Haven, CT)) prior to isolation of the BMC for analysis [1, 2]. All TCDD exposures were completed in 12 hours, while PAHs were tested for up to 48 hours.…”

“…People are chronically exposed to polycyclic aromatic hydrocarbons (PAHs) in multiple ways ranging from cigarette smoke to diesel fumes and coal tars [1]. Many PAHs are converted by metabolism at P450 cytochromes (Cyps) to highly reactive and mutagenic dihydrodiol epoxide metabolites [2].…”