Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene.

Abstract

We gratefully acknowledge the expertise of S. Lair in performing the histopathologic analysis. R. Matusik provided the LPB-CAT mice; the mE-RABP-CAT mice were a gift from J.-J. Lareyre, M.-C. Orgebin-Crist, and R. Matusik.This work was funded by the National Cancer Institute of Canada.Received 2 Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.

Internal exposure to pollutants and sex hormone levels in Flemish male adolescents in a cross-sectional study: associations and dose–response relationships

“…For most exposureresponse associations in our study, a supra-linear relationship was observed, with relatively more intense responses (steeper dose-response curves) at exposures below the median. Others have made similar observations, for instance regarding dioxins in humans (Eskenazi et al, 2005) or HCB in animals (Ralph et al, 2003). Hence, one might speculate that the observed biological and health effects result from interactions with receptors, constituting a xeno-hormonal rather than a less-specific toxic effect.…”

Increased cancer burden among pesticide applicators and others due to pesticide exposure

“…42 For example, in vivo and in vitro data from mice and cultured cells suggest that low levels of hexachlorobenzene (HCB) can weakly agonize androgen action and thus enhance androgen signaling, whereas high levels of HCB interfere with androgen signaling. 31 In addition, genotoxic mechanisms may also be in play for OCs. For instance, the OC lindane was found to induce micronuclei in cultured human prostate cells following treatment at very low concentrations (10 -12 -10 -10 M) for 24 hours.…”

Organochlorine pesticides and prostate cancer, Is there an association? A meta-analysis of epidemiological evidence

“…Even more sophisticated roles for DDE have been displayed as its facilitating transcriptional activation of selected tumorderived androgen receptor mutants and thus a role in androgen deprivation resistant PC [14]. Endocrine disruption was also shown for HCB by enhancing androgen action at low doses and inhibiting it at high doses [15]. HCH was also found to possess endocrine disrupting potential by increasing blood level of estradiol.…”

“…Interference with endogenous estrogenic or androgenic pathways as agonists or antagonists has been proposed [15]. However, some authors questioned the association between endocrine disrupting compounds and carcinogenesis due to the limited available supporting evidence [16,17].…”