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Validation of test strategies for the identification of adverse effects of chemicals on the human fetal ovarian development


   School of Medicine, Medical Sciences & Nutrition

  , Dr Severine Mazaud-Guittot  Monday, October 03, 2022  Funded PhD Project (European/UK Students Only)

About the Project

The European FREIA project, which both supervisors are part of, is specifically designed to address how female reproductive health can be safeguarded from endocrine disrupting chemicals (EDCs).

This project aims to provide better test methods to identify human-made chemicals that disturb hormones and their actions on development and function of the reproductive system in women. In the first phase of FREIA, the “Discovery phase”, we looked for biological characteristics that can be linked to female reproductive toxicity and test methods to measure this. For this, we used two well-known endocrine disrupting chemicals: diethylstilbestrol (a potent oestrogen receptor activator) and ketoconazole (a blocker of steroid hormone production). We have found some clear effects of endocrine disrupting chemicals on oocytes and hormonal processes that are linked to female reproductive health. These findings may pinpoint relevant test methods to support identification of endocrine disrupting chemicals that are harmful to female reproductive health. In the second phase of Freia, the ‘Testing Phase”, fetal ovaries will be exposed to chemicals that are found in real life human body fluids and fetal organs, and previously identified markers will be challenged for validation of test methods.

Over the last 3 years, we used two model chemicals and screened for molecular and cellular responses of human fetal ovaries after exposure in organotypic culture by both classical targeted and untargeted approaches. By using these two strong model chemicals, we designed and proposed a decision tree for experimental strategies to evaluate the different parameters of proper ovarian development, including growth, cell health, germ cell differentiation, and endocrine function. This PhD project aims to extend the second part of the FREIA project, the Testing Phase, using biomarkers previously identified with chemicals, especially endocrine disrupting chemicals, identified by other partners of the consortium, and likely to be of concern for the development of the ovary, and ultimately reproduction of women.

The student will have to use all the transcriptomic resources obtained so far, not only those specific to the Freia project, to refine this experimental strategy decision tree, in particular by using the ToxSign analysis tool developed by Irset. The student will use organotypic cultures, data/knowledge mining (including resources like ToxCast and our own datasets obtained during the discovery phase) and histological, cellular and molecular biology methods to evaluate the sensitivity of endocrine disrupting chemical-vulnerable pathways in human fetal ovarian development. The student will identify the suitability of biomarkers for different classes and combinations of endocrine disrupting chemicals, and the best-fit methods to evaluate key events leading to adverse effects. Building on the identification of links between molecular events and cellular effects, the student will be involved in the development of Adverse Outcome pathways in AOPwiki. The outputs will be both scientific and applied in that AOPs for female reproductive disruption are not well addressed in OECD tests and better suited, more predictive and sensitive tests are needed.

Desired background of student:

Good knowledge of reproductive biology and toxicology are required, as well as technical skills in the study of RNAs, and/or cell culture, and cytometry. The candidate will be associated with high throughput studies, an interest in analytical approaches is therefore preferable. 

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at Master’s level.

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APPLICATION PROCEDURE:

  • Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php
  • You should apply for Medical Sciences (PhD) to ensure your application is passed to the correct team.
  • Please clearly note the name of the lead supervisor and project title on the application form. If you do not mention the project title and the supervisor on your application it will not be considered for the studentship.
  • Please include a personal statement, an up-to-date copy of your academic CV, and relevant educational certificates and transcripts (Undergraduate and postgraduate (if applicable)).
  • Please note: you DO NOT need to provide a research proposal with this application
  • CV's submitted directly through a FindAPhD enquiry WILL NOT be considered.
  • General application enquiries can be made to  

Funding Notes

This 36 Month, fully funded PhD is a co-tutelle arrangement between Universities of Rennes (France) and Aberdeen (UK).
This opportunity is open to UK and EU students and includes funding to cover tuition fees and research costs. A stipend at the UKRI rate is also provided (£16,062 for the 22/23 academic year) .

References

• Connan-Perrot S, Léger T, Lelandais P, Desdoits-Lethimonier C, David A, Fowler PA, Mazaud-Guittot S. Six Decades of Research on Human Fetal Gonadal Steroids. Int J Mol Sci. 2021 Jun 22;22(13):6681. doi: 10.3390/ijms22136681. PMID: 34206462. Review.
• Duursen MBMV, Boberg J, Christiansen S, Connolly L, Damdimopoulou P, Filis P, Fowler PA, Gadella BM, Holte J, Jääger K, Johansson HKL, Li T, Mazaud-Guittot S, Parent AS, Salumets A, Soto AM, Svingen T, Velthut-Meikas A, Wedebye EB, Xie Y, Berg MVD. Safeguarding Female Reproductive Health against Endocrine Disrupting Chemicals-The FREIA Project. Int J Mol Sci. 2020 May 1;21(9):3215. doi: 10.3390/ijms21093215. PMID: 32370092. Review.
• Leverrier-Penna S, Mitchell RT, Becker E, Lecante L, Ben Maamar M, Homer N, Lavoué V, Kristensen DM, Dejucq-Rainsford N, Jégou B, Mazaud-Guittot S. Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo. Hum Reprod. 2018 Mar 1;33(3):482-493. doi: 10.1093/humrep/dex383. PMID: 29408962

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