title: Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DNA damage in rats.
abstract: Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies.
authors.affiliation: Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamada
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.forename: Minoru
authors.initials: M
authors.lastname: Kato
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tago
authors.forename: Mistuaki
authors.initials: M
authors.lastname: Kitano
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000139:chemically induced; D002273:Carcinogens / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000009:adverse effects*; D065633:Cytochrome P-450 CYP1B1; D004249:DNA Damage / Q000187:drug effects; D004052:Diethylnitrosamine / Q000009:adverse effects; D007564:Japan; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D009498:Neurotoxins / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001152:Arsenicals; C494828:Bax protein, rat; D002273:Carcinogens; D002619:Chemical Warfare Agents; D009498:Neurotoxins; D018336:Receptors, Aryl Hydrocarbon; D051028:bcl-2-Associated X Protein; D004052:Diethylnitrosamine; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; C493087:diphenylarsinic acid
keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; 7,12-dimethylbenz[a]anthracene; 8-OHdG; 8-hydroxy-2′-deoxyguanosine; AhR; Aryl hydrocarbon receptor; B[a]P; COX-2; CYP; CYP1B1; DEN; DMBA; DPAA; Diphenylarsinic acid; GST-P positive foci; Hepatocarcinogenicity; Oxidative DNA damage; PCB; PCNA; Rat; TCDD; aryl hydrocarbon receptor; benzo[a]pyrene; cyclooxygenase-2; cytochrome P450; diethylnitrosamine; diphenylarsinic acid; glutathione S-transferase placental form positive foci; polyhalogenated biphenyl; proliferating cell nuclear antigen