Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: proliferative and inflammatory disorders and a possible role of androgens.
In the present study we evaluated the toxic effects on the male adult rat prostate of DBP exposure during fetal and lactational periods, because although many studies have addressed the influence of phthalates on the male reproductive system, only a few have discussed their possible effects on prostate development. Pregnant females were distributed into two experimental groups: Control (C) and Treated (T). The females of the T group received DBP (100mg/kg, by gavage) from gestation day 12 to postnatal day 21, while C rats received the vehicle (corn oil). In adulthood (90 days old), the animals were euthanized. The serum and testicular testosterone levels were measured. Ventral prostate was removed and weighed. Distal segment fragments of the ventral prostate were fixed and processed for histochemistry and immunohistochemistry to detect androgen receptor (AR) and Ki67 antigens. Protein extraction from ventral prostate fragments was performed for AR immunoblotting and Gelatin zymography for MMP-2 and MMP-9 (MMP, metalloproteinase). Stereological and histopathological analyses were also performed. Serum and testicular testosterone levels and prostate weight were comparable between groups. In the T group the relative proportions (%) of epithelial (C=32.86; T=42.04*) and stromal (C=21.61; T=27.88*) compartments were increased, while the luminal compartment was decreased (C=45.54; T=30.08*), *p<0.05. InT, disseminated inflammatory infiltrate in the stroma, associated or not with epithelial dysplasia and PIN (Prostatic Intraepithelial Neoplasia), was observed. Increases in AR expression, proliferation index and metalloproteinase 9 (MMP-9) activity were noted in T animals. In some T animals, collagen fibrils accumulated adjacent to the epithelium. As far as we are aware, this is the first report in the literature showing that phthalates could play a role in proliferative and inflammatory disorders of the rat prostate.
Scarano
Wellerson Rodrigo
WR
Department of Morphology, Institute of Biosciences, UNESP, Botucatu, SP, 18618-000, Brazil. wrscarano@yahoo.com
Toledo
Fabíola Choqueta de
FC
Guerra
Marina Trevizan
MT
de Campos
Silvana Gisele Pegorin
SG
Júnior
Luís Antonio Justulin
LA
Felisbino
Sérgio Luis
SL
Anselmo-Franci
Janete A
JA
Taboga
Sebastião Roberto
SR
Kempinas
Wilma De Grava
Wde G
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors
D019394:Ki-67 Antigen; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; D013739:Testosterone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9