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

Abstract

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.

Genistein reduces the noxious effects of in utero bisphenol A exposure on the rat prostate gland at weaning and in adulthood

“…This result is in agreement with other rodent studies which indicates that prenatal or neonatal exposure of male rat and mice to low doses of estradiol and other estrogenic chemicals like BPA and offspring can lead to androgen sensitivity and consequently to an increased expression of AR in the prostate in pubertal and young adults rodents (Nagel et al, 1997;Gupta, 2000;Brandt et al, 2014). Furthermore, in a previous study we observed that estrogen supplementation even in a lowandrogen environment (after castration) increased AR expression in Mongolian gerbil ventral prostate through paracrine signaling mechanisms involving ER-a (Scarano et al, 2009). Maternal dietary GEN tended to normalize AR expression in the VL in male offspring from dams exposure to low-dose BPA.…”

“…Previous reports have shown that exposure to estradiol may increase the synthesis of collagen in the stromal cells and make collagen bundles thicker in rodent prostate (Tilley et al, 1989;Prins et al, 2007;Scarano et al, 2005Scarano et al, , 2008. However, serum levels of estradiol on PND21 did not differ among the experimental group but some toxicological studies in which EDs were administered during pregnancy showed that hormone levels tend to normalize after exposure; however, the tissue-specific effects remain (Putz et al, 2001;Scarano et al, 2009). A significant reduction in the cell proliferation index related to the partial recovery of prostatic architecture in the VP was observed on PND21.…”

Di-n-Butyl Phthalate (DBP) Exposure Induces Oxidative Damage in Testes of Adult Rats

“…Although there is insufficient data for DBP effects on human reproduction, some studies in rodents have reported the influence of DBP on the male reproductive system [Alam et al 2010;Scarano et al 2009;Hoshi and Ohtsuka 2009]. To date, however, the mechanisms of reproductive toxicology of DBP are still unclear and need to be further studied.…”

Di-n-butyl phthalate (DBP) exposure induces oxidative stress in epididymis of adult rats

“…Recently, there are growing concerns regarding the toxicity of DBP exposure on male reproduction (Alam et al, 2010;Scarano et al, 2009). Reported reproductive effects of DBP include alteration in activities of steroidogenic enzymes, alteration in testosterone metabolism and decreased levels of plasma testosterone; they are suspected of acting as endocrine distuptors that have the potential to modify normal endocrine function (Hirosawa et al, 2006;Xiaofeng et al, 2009).…”