The postdoc position is open in the framework of two projects led by MUSCA, the OVOPAUSE ANR project and the OVOTOX FC3R project, gathering researchers from different institutions and scientific background (applied mathematics, developmental and reproductive biology, ecotoxicology).
The position is an opportunity to be involved in a strongly interdisciplinary consortium, and to strengthen experience in mathematical and computational biology by working on the coupling of population dynamics models with compartmental pharmacokinetic models. The contract is expected to start in the beginning of year 2025, from January to March.
Apply for this position at https://recrutement.inria.fr/public/classic/fr/offres/2024-08077
The impact of micropollutants on living organisms is a major concern, whether at the individual or population level. Due to their living environment and their physiology, fish are particularly exposed to these micro-pollutants and in particular to endocrine disruptors (ED). They therefore constitute sentinel species for detecting and understanding the multiscale reprotoxic effects of EDs and their adverse outcomes on the reproductive fitness from the individual up to the population levels. The field of toxicology, and more generally eco-toxicology, has recently acquired methodological tools, such as qAOP (quantitative Adverse Outcome Pathways), based on dynamic models with quantitative outputs to rigorously assess the effects of EDs from available experimental data and knowledge (Conolly et al. 2017). qAOP models can predict ED effects in silico and be used both for basic research and regulatory purposes, while limiting the use of laboratory animals.
The postdoc work will be dedicated to enriching a qAOP model developed by the hosting team and collaborators. The first task will consist in coupling a size-structured (PDE-based) mechanistic model of oogenesis (the developmental process leading to the release of a fertilizable femate gamete), considering all maturation stages and their control (Bonnet et al. 2020, Ballif et al. 2024), with a physiologically-based pharmacokinetic (compartmental ODE-based) model representing the hormonal dynamics within the reproductive (hypothalamo-pituitary-gonadal) axis (Pery et al. 2014, Ly et al. 2023). The coupling will be based on careful mapping of functions involved in the different models, addition of missing variables when needed, and timescale separation when possible to enforce model parcimony. The second task will be to design appropriate numerical schemes to simulate the model in both physiological and toxicological situations (exposure to EDs) and perform an extensive parameter estimation and sensitivity/identifiability analysis. The calibrated coupled models will enable a detailed assessment of reprotoxic effects, in particular long-term effects and rebound/compensation mechanisms affecting the oocyte population and hormonal feedback loops. If time allows, and according to the interest of the post-doctoral candidate, we will tackle a qualitative analysis of the coupled model to shed light onto the structural influence of parameters on the model behavior and the related impact on the reproductive function.
References
G. Ballif, F. Clément and R. Yvinec, Nonlinear compartmental modeling to monitor ovarian follicle population dynamics on the whole lifespan, J. Math. Biol., 89:9, 2024.
C. Bonnet, K. Chahour, F. Clément, M. Postel, R. Yvinec. Multiscale population dynamics in reproductive biology: singular perturbation reduction in deterministic and stochastic models. ESAIM Proc. Surveys, 67: 72-99, 2020.
R.B. Conolly, G.T. Ankley, W.Y. Cheng, M.L. Mayo, D.H. Miller, E.J. Perkins, D.L. Villeneuve, K.H. Watanabe. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol., 51(8):4661–4672, 2017.
T.-K. Ly, J. De Oliveira, E. Chadili, K. Le Menach, H. Budzinski, A. James, N. Hinfray, R. Beaudouin. Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model, 04 December 2023 (preprint available at 10.21203/rs.3.rs-3580808)
A. Pery, J. Devillers, C. Brochot, E. Mombelli, O. Palluel , B. Piccini , F. Brion, R. Beaudouin. A Physiologically - Based Toxicokinetic Model for the Zebrafish Danio rerio. Environ. Sci. Technol., 55848: 781-790, 2014.
