Gestational and lactational exposition to Di-N-butyl-phthalate (DBP) increases inflammation and preneoplastic lesions in prostate of wistar rats after carcinogenic N-methyl-N-nitrosourea (MNU) plus testosterone protocol.
In the present study, it was evaluated the susceptibility of prostatic lesions in male adult rats exposed to Di-N-butyl-phthalate during fetal and lactational periods and submitted to MNU plus testosterone carcinogenesis protocol. Pregnant females were distributed into four experimental groups: CN (negative control); CMNU (MNU control); TDBP100 (100 mg/kg of DBP); TDBP500 (500 mg/kg of DBP). Females from the TDBP groups received DBP, by gavage, from gestation day 15 (GD15) to postnatal day 21 (DPN21), while C animals received the vehicle (corn oil). CMNU, TDBP100, and TDBP500 groups received a single intraperitoneal injection of MNU (50 mg/kg) on the sixth postnatal week. After that, testosterone cypionate was administered subcutaneously two times a week (2 mg/kg) for 24 weeks. The animals were euthanized on PND220. Distal segment fragments of the ventral (VP) and dorsolateral prostate (DLP) were fixed and processed for histopathological analysis. Protein extracts from ventral prostate were obtained, and western blotting was performed to AR, ERα, MAPK (ERK1/2), and pan-AKT. Stereological analysis showed an increase in the epithelial compartment in TDBP100 and TDBP500 compared to CN. In general, there was increase in the incidence of inflammation and metaplasia/dysplasia in the DBP-treated groups, mainly in DLP, compared to CN and CMNU. Proliferation index was significant higher in TDBP500 and PIN (prostatic intraepithelial neoplasia) was more frequent in this group compared to CMNU. Western blot assays showed an increase in the expressions of AR and MAPK (ERK1/2) in the TDBP100 compared to CN, and ERα and AKT expressions were higher in the TDBP500 group compared do CN. These results showed that different doses of DBP during prostate organogenesis in Wistar rats could increase the incidence of premalignant lesions in initiated rats inducing distinct biological responses in the adulthood. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1185-1195, 2016.
Graduate Program in General and Applied Biology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
André R
AR
Peixoto
Graduate Program in General and Applied Biology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Talita M
TM
Santos
Graduate Program in General and Applied Biology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Joyce Z
JZ
Brandt
Department of Morphology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Flávia K
FK
Delella
Department of Morphology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Bianca F
BF
Gonçalves
Department of Biology, Institute of Biosciences, Letters and Exact Sciences; UNESP, São José do Rio Preto, SP, Brazil.
Silvana G P
SG
Campos
Department of Biology, Institute of Biosciences, Letters and Exact Sciences; UNESP, São José do Rio Preto, SP, Brazil.
Sebastião R
SR
Taboga
Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil.
Wagner J
WJ
Favaro
Department of Anatomy, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Raquel F
RF
Domeniconi
Department of Morphology, Institute of Biosciences, UNESP, Botucatu, SP, Brazil.
Wellerson R
WR
Scarano
D000818:Animals; D015153:Blotting, Western; D003993:Dibutyl Phthalate / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007774:Lactation; D008297:Male; D018811:Maternal Exposure; D008770:Methylnitrosourea / Q000633:toxicity*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; D013739:Testosterone; D008770:Methylnitrosourea; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C016131:testosterone 17 beta-cypionate
DBP; MNU plus testosterone; inflammation; preneoplastic lesions; prostate