Prostate cancer is the third most common cancer in older men and reproductive disorders and cancers are increasing in younger men and boys. Scientific research has revealed that exposure to endocrine disrupting environmental pollutants may be partly responsible for these trends and this has led to changes in legislation concerning the safety testing of chemicals involving increased numbers of animal tests. The rat Hershberger assay, originally developed to identify the hormones involved in male sexual development, is the gold standard pre-clinical test used both in the development of drugs used to treat hormone-dependent male cancers and for screening suspected endocrine disrupting chemicals for androgenic and anti-androgenic activity. This proposal aims to explore the possibility that snails might be good model organisms for screening chemicals for androgenic and anti-androgenic effects. Our hypothesis is that the reproductive organs and accessory sex glands of snails are functional analogues of parts of the mammalian male reproductive organs and so respond to androgenic and anti-androgenic chemicals in a similar fashion to their mammalian counterparts. The notion that molluscs could be used as potential surrogates for mammals in reproductive tests is supported by the many features their reproductive systems share with those of mammals, from the molecular level to gross anatomy. We will compare the response of reproductive tract of the mollusc (B. glabrata) exposed to androgenic chemicals (in the presence and absence of clinical anti-androgenic drugs or endocrine disrupting chemicals with different modes of action) to known effects of the same chemicals reported in vertebrate tests at different levels of complexity. We will characterise changes in the morphology of reproductive organs, changes in androgen-dependent antigenic markers (such as prostate specific antigens; PSA) with labelled PSA-antibodies on histological sections, and at the genomic level we will characterise differentially expressed genes in tissues of exposed snails using Suppression Subtractive Hybridisation (SSH) approaches combined with the use of a B. glabrata microarray. A properly validated, mechanistically relevant mollusc test that can objectively quantify the response of the male reproductive system to androgens and anti-androgens will have the potential to at least partially replace the use of the rat Hershberger Assay and would be expected to lead to a reduction in the numbers of vertebrate animals needed in reproductive toxicity tests and possibly carcinogenicity testing and, consequently, to a refinement of test protocols in general, minimizing vertebrate animal usage.
Kaur S et al. (2015). The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms. PLoS One 10(4):e0121259. doi: 10.1371/journal.pone.0121259
Principal investigatorDr Susan Jobling
Co-InvestigatorDr Catherine Jones
Dr Leslie Robert Noble
Dr Edwin John Routledge