title: 7,12-Dimethylbenz(a)anthracene-induced myelotoxicity differs in mice selected for high or low acute inflammatory response: relationship with aryl hydrocarbon receptor polymorphism.
abstract: Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.
authors.affiliation: Laboratório de Imunogenética, Instituto Butantan, Av Dr Vital Brazil, 1500, CEP 05503-900, São Paulo, SP, Brazil. Email: orlando.ribeiro@butantan.gov.br.
authors.forename: Iana Suly Santos
authors.initials: IS
authors.lastname: Katz
authors.forename: Layra Lucy
authors.initials: LL
authors.lastname: Albuquerque
authors.forename: Alessandra Paes
authors.initials: AP
authors.lastname: Suppa
authors.forename: Débora Mathias
authors.initials: DM
authors.lastname: de Siqueira
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rossato
authors.forename: Graziela Batista
authors.initials: GB
authors.lastname: da Silva
authors.forename: José Ricardo
authors.initials: JR
authors.lastname: Jensen
authors.forename: Nancy
authors.initials: N
authors.lastname: Starobinas
authors.forename: Wafa Hanna Koury
authors.initials: WH
authors.lastname: Cabrera
authors.forename: Marcelo
authors.initials: M
authors.lastname: De Franco
authors.forename: Primavera
authors.initials: P
authors.lastname: Borelli
authors.forename: Olga Martinez
authors.initials: OM
authors.lastname: Ibañez
authors.forename: Orlando Garcia
authors.initials: OG
authors.lastname: Ribeiro
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001855:Bone Marrow Diseases / Q000139:chemically induced* / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000096:biosynthesis; D002460:Cell Line; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018336:Receptors, Aryl Hydrocarbon; D009569:Nitric Oxide; D015127:9,10-Dimethyl-1,2-benzanthracene; D006861:Hydrogen Peroxide
keywords: AhR; Biogel; PMN; bone marrow; inflammation