(MRC DTP) Glyphosate and N-nitrosoglyphosate toxicity in C. elegans
Glyphosate (N-(phosphonomethyl)glycine): GLY) is a systemic herbicide that is in extensive worldwide use in agriculture, amenity and garden settings1. The potential carcinogenic effects of GLY exposure are controversial2 but there is also increasing evidence that commercial formulations containing GLY may be more toxic than GLY itself. GLY technical concentrates can contain, at low levels, N-nitrosoglyphosphate (NGLY). Moreover, following GLY uptake (adsorption/inhalation/ ingestion) endogenous nitrosation to NGLY is expected to occur. NGLY is a secondary nitrosamine and these compounds are typically but not exclusively genotoxic and carcinogenic3. NGLY toxicity has been little studied but we would expect NGLY to be metabolised by CYP 450s to form toxic intermediates that react with nuclear and mitochondrial DNA to cause mutations as well as disrupting the epigenome to affect mitochondrial function, cell death and potentially induce oxidative stress. Counterintuitively, a mild oxidative stress can improve outcomes such as life expectancy and stress resistance. Interestingly, increased life span and stress resistance functions can be epigenetically inherited in the animal system C. elegans4. The aim of this study is determine whether (i) NGLY is more toxic than GLY in C. elegans, (ii) NGLY exposure results in the formation of chemically reactive intermediates causing genetic/epigenetic changes that affect stress responses and (iii) to further examine biological pathways of response to GLY and NGLY to better understand toxicological differences. This will be assessed by life span measurement, stress assay survival, and epigenetic inheritance of stress responses as well as by the detection of DNA damage and the consequences of DNA damage in vitro and in C. elegans. C. elegans has a become a prominent model for research4,5. It is an animal system with a fast life cycle (3 days from an embryo to an adult) and an average life span of 2 weeks. Crucially, most human ageing and stress-related pathways are conserved in C. elegans5. It is also a transparent animal in which Green Fluorescent Protein reporter assays can easily be performed using microscopy. Taken together, C. elegans is a powerful animal model that can examine genetic/epigenetic changes caused by toxic compounds such as NGLY and GLY, which may affect stress response pathways.
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.
1Duke SO. Pest Manag Sci 2018;74:1027-34;2 Davoren MJ and Schiestl RH. Carcinogenesis 2018; 39: 1207-1215; 3 Rostkowska K et al. Pol J Environ Sci 1998; 7:321-5; 4 Denzel MS et al. Mech Ageing Dev 2019; 177:4-21. 5 Reid Hunt P. J Appl Toxicol 2017;37:50-9.