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The environmental contaminants, PCBs impact on androgen receptor action and prostate growth and development

University of British Columbia

Poly chlorinated biphenyls (PCBs) are synthetic chemicals that were used in industrial lubricants and household goods until they were banned in open systems in North America in 1977, after millions of tons were manufactured. PCBs are currently widespread major environmental contaminants that persist in the environment and due to their lipophilic nature, bioaccumulate-exponentially up the food chain. All humans, particularly in industrialized countries, carry a burden of PCBs primarily in their adipose tissue. Studies in laboratory animals, wildlife, and humans exposed to PCB spills suggest that PCBs interfere with normal steroid hormone action. Therefore, PCBs and other persistent organochlorines, pose a risk to human health as endocrine disrupting compounds that may target hormone sensitive organs such as the prostate which require steroid hormones for appropriate growth and differentiation. In utero exposure .to compounds that affect steroid hormone action can be the most detrimental to development. In this study the influence of PCBs on the androgen axis in vitro and in vivo were examined. The effects of PCBs on androgen and glucocorticoid regulated reporter gene expression in a prostate cell line, and the ability of PCBs to influence binding of endogenous hormones to the androgen receptor (AR) were tested. Aroclor 1254 acted as a weak androgen receptor agonist, and Aroclor 1254, Aroclor 1242, Aroclor 1260, PCB 42, and PCB 31 were antagonistic to androgen activity at high concentrations relative to natural ligand concentrations. PCB 42 was an additive glucocorticoid receptor (GR) agonist and increased reporter activity to a level 150% higher at 10000 nM than at 0 nM PCB 42. Aroclor 1254 and PCB 42 significantly reduced the levels o f DHT binding to the androgen receptor by 25% and 50% respectively, at 1000 n M . Both these compounds reduced DHT levels by 90 to 95% at 10000 nM. The treatment of mice transgenic for a prostate specific probasin promoter driven a CAT reporter gene, with Aroclor 1254 resulted in changes in prostate growth and development. In a single dose level study, mice were treated in utero and until four weeks (prepubertal) and eight weeks (post pubertal) of age with 10 mg/kg/day of Aroclor 1254. Additionally, in a dose response study, mice were treated in utero and until eight weeks of age with 10, 20, and 40 mg/kg/day. Prostate, testis, epididymis, heart, kidney, and liver weights were measured for comparison between groups. Results indicated that Aroclor 1254 has the capacity to reduce prostate weight and increase liver weight (both normalized for body weight) in a dose dependent manner. Finally, prostatic CAT activity was measured. This PCB mixture significantly reduced CAT activity in eight week old treatment mice in the single dose level study. Histology of prostate and liver were also examined in the dose response group. Histological alterations included dose related changes in liver vacuolization, as well as lymphocytic infiltrations and an increase in the presence of predominantly dilated acini in the prostate in a dose dependent manner. These findings demonstrate that PCBs can influence steroid hormone action through the androgen axis in vitro, and interfere with androgen-regulated gene expression in vivo.

Thesis/Dissertation

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2009-07-13

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http://hdl.handle.net/2429/10766

Pathology

University of British Columbia

UBCV

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