(MRC DTP) Glyphosate and N-nitrosoglyphosate toxicity in C. elegans.

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.

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships