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Abstract
The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR). TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR) expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.
Highlights
According to the Agency for Toxic Substances and Disease Registry (ATSDR) 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) is known to be a developmental toxicant in animals, resulting in kidney, skeletal and immune system defects in the offspring of animals exposed during pregnancy [1].Because studies have shown an association between 2,3,7,8-TCDD and soft-tissue sarcomas, lymphomas, and stomach carcinomas in humans, the U.S Environmental Protection Agency (EPA)has classified 2,3,7,8-TCDD as a probable human carcinogen (Group B2) [2,3]
Our results show that TCDD exposure does not induce aryl hydrocarbon receptor (AhR) or androgen receptor (AR) degradation in C4-2 cells
LNCaP cells have higher AR protein levels that are diminished by TCDD exposure and enhanced by treatment with synthetic androgen R1881
Summary
Because studies have shown an association between 2,3,7,8-TCDD and soft-tissue sarcomas, lymphomas, and stomach carcinomas in humans, the U.S Environmental Protection Agency (EPA). Has classified 2,3,7,8-TCDD as a probable human carcinogen (Group B2) [2,3]. Ambient measurements confirm that environmental TCDD contamination is widespread and it is the most toxic halogenated aromatic hydrocarbon [4]. There is significant concern about TCDD exposure from such diverse sources as municipal solid waste incinerators, pulp and paper mills, and contaminated fish and soil which could lead to serious health effects [3]. Long-term TCDD exposure can lead to the development of tumors of the liver, thyroid, lung, prostate, skin, oral cavity, ovary and other sites in animal experiments [6,7]. TCDD is a multisite carcinogen and dioxins are extremely persistent and bioaccumulative.
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