There is growing concern that the health of many species, including humans, may be threatened by an increasing burden of environmental contaminants. Many researchers around the world have made discoveries demonstrating endocrine activity in an array of contaminants to which humans and wildlife may be exposed. Although much of the focus has been upon interference with estrogen activities, there is growing evidence for interaction with thyroid, androgen and other endocrine axes. This study investigates the potential of a selection of environmental contaminants, including PCBs, pulp mill by-products, pesticides, and alkylphenols, to interfere with endocrine processes. Using tissue culture assays, we have investigated the ability of these compounds to interfere with steroid hormone signalling pathways and have focused on the underlying mechanism of androgenic effects observed through further in vitro assays. A transgenic mouse model was used to explore the impact of compounds of particular interest upon the development and function of androgen regulated tissues in vivo. Several of the test compounds possessed endocrine activity, most frequently manifest as antagonism of the androgen receptor (AR). Amongst the pesticides tested both the o,p′- and p,p′-isomers of dichlorodiphenyltrichloroethane (DDT) and p,p′-dichlorodiphenyldichloroethylene (DDE) were AR antagonists. Nonylphenol and a short chain ethoxylate (N-10) as well as four Aroclor mixtures and a set of congener components selected from them were also found to antagonise AR. Only hexachloroberizene and black liquor, a pulp mill by-product, exhibited androgenic effects in vitro . Estrogen receptor was antagonised by β-endosulfan and p,p′-DDE, while o,p ′-DDT, nonylphenol and octylphenol all acted as estrogen mimics. The glucocorticoid receptor was antagonised by β-endosulfan, while being stimulated by o,p′-DDT, the alkylphenol ethoxylate N-100 and PCB congener 42. Nonylphenol, Aroclor 1254 and one of the PCB congeners were tested by oral administration in mice and all produced physiological effects, with Aroclor 1254 in particular exhibiting clear anti-androgenic properties in vivo. Nonylphenol caused an elevation in serum thyroid hormone along with an increase in testis size and anogenital distance. In addition, the nonylphenol treatment increased the expression of an androgen responsive CAT reporter gene that is expressed specifically in the prostate. The PCB mixture Aroclor 1254 caused a decrease in prostate weight, and CAT reporter gene expression but precocious maturation of the prostate gland. In contrast the congener PCB 42 had no significant effects upon the prostate but caused increased testis weight and impacted on spermatogenesis in the epididymis. These results emphasize the sensitivity of the endocrine system and the diverse physiological functions which it regulates. They also demonstrate the ligand promiscuity of the steroid receptors and reinforce the need to evaluate the endocrine potential of substances humankind introduces into the environment. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/10304 |
| Date | 14 November 2018 |
| Creators | Cowell, Simon Piers |
| Contributors | Glickman, Barry W., Nelson, C. C. |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
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