Integrative systems toxicology for human health
- Autores: Raju Prasad Sharma
- Directores de la Tesis: Vikas Kumar (dir. tes.), Marta Schuhmacher Ansuategui (codir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Maria Teresa Colomina Fosch (presid.), Nicoline Vermeulen (secret.), Bas Teusink (voc.)
- Programa de doctorado: Programa de Doctorado en Nanociencia, Materiales e Ingeniería Química por la Universidad Rovira i Virgili
- Materias:
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- Resumen
In an industrialised economy, large amount of the chemicals are produced and released into the environment. The accumulations of these chemicals in the ecosystem and their subsequent exposure are suspected of causing adverse effects on human’s health. REACH (Registration, Evaluation, Authorisation, and Restriction of Chemicals) and 3Rs (Replacement, Reduction and Refinement) principle is proposed to regulate the chemicals production and their uses by the ECHA and the EFSA respectively. Both principles are focused on improving the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances. Simultaneously it also aims to alternative to animal testing by development of in vivo and in-silico tools and incorporation of integrated assessment and testing approaches (IATAs) etc. The early identifications of chemical induced adverse effects pose several challenges such as; an inheritance complexity within the biological system and chemical’s complex mechanism or the complex responses of organism over different life stage or time scales. Emerging high-throughput analysis, OMICS and several in-silico tools such as PBPK, PD, Systems biology and AOPs offer an opportunity to understand the biological complexity and their multilevel connectivity. Along with the development of new tools and techniques in toxicological research, it is necessary to have a continuous re-evaluation of existing data, curation, data integration, and knowledge-based translation that might able to solve many current challenges in this field. In addition, there is a paucity of research that integrates in-vitro, in-vivo, and several in-silico models into one platform to directly tie the result to a predictive adverse outcomes model.
The objective of the current thesis was to develop an Integrative Systems toxicology framework to quantitatively understand the adverse effects of chemicals on a biological system, from its exposure to subsequently molecular and physiological alteration, through the integration of exposome-internal exposure- molecular/cellular response to the adverse effect. This aimed at mechanistic understanding of chemical’s interaction with living systems versus conventional empirical end points and animal based testing. This approach integrates all the event such as chemical exposures, physiology, pharmacokinetics, pharmacodynamics, and biological response etc.
In chapter I, Literature review was done to understand the mechanisms of action of EDCs which includes the interaction of chemicals with molecular receptors, enzymes, proteins, gene regulatory mechanism or epigenetic process thus affecting the biological system, including the window of exposure. This chapter also investigates the normal endogenous pathway of the hormone to understand the physiology dependent EDCs' action. Then, the Classification of EDCs was done based on their target organs, hormones, biomolecule (target) and adverse outcomes (response). Finally, grouping strategy based on similar adverse outcomes was proposed. This chapter addressed many challenges like multiple mechanisms, delayed response (time lag between exposure to adverse outcomes), dynamic interactions involving crosstalk and common mechanisms (complex mechanisms), and transgenerational effect etc. in the quantitative risk assessment. Finally, Integrative risk assessment framework consisting exposome-internal exposure-biological effect to the adverse outcomes was proposed. This included the use of PBPK model, PD (pharmacodynamics model) and coupling of these two models.
Chapters II included the development and validation of PBPK model in adult for Di-2-ethylhexyl phthalate (DEHP) and Flutamide, both have been categorized under the EDCs. The model for DEHP included four several metabolites namely mono-(2-ethylhexyl) phthalate (MEHP), 5-OH MEHP, 2-ethyl-5-carboxypentyl phthalate (5-cx MEPP) and 5-oxo MEHP. An IVIVE tool has successfully been used in connection with a PBPK to derived in-vivo kinetics from in vitro studies using biologically appropriate scaling. A local parametric sensitivity analysis was done and the most uncertain yet influential parameters were distributed statistically for Monte Carlo simulations for model uncertainty analysis. Then the model was evaluated against the published independent data on plasma and urine concentrations of DEHP metabolites for different dosing scenarios.
Development of flutamide PBPK model includes bottom-up, top-down and cross-species extrapolation approach. First, the model was developed in the rats and then extrapolated to the humans. The rat model was evaluated against the experimentally observed data over 7 compartments and the model performed fairly: the values predicted by the median model were less than a factor of 10 away from the average experimental value, for most tissues. The extrapolation of the model to predict flutamide kinetics in humans for two different scenarios of dosing (single and multiple) was also in good agreement with the observed data.
Chapters III focused on the development of a Pregnancy PBPK model for BPA that included the fetus body as a sub compartment into the model structure. First, the adult PBPK model was developed and validated with the human BPA toxicokinetic data. This validated human PBPK model was extended to develop a P-PBPK model which included the physiological changes during pregnancy and the fetus sub-model. The developed P-PBPK model is in concordance with biomonitoring data and showed that BPA readily transferred to fetal serum and amniotic fluid after mother's exposure. Deconjugation in placenta and fetus body causing increased BPA exposure in early fetal life. Importantly, free BPA in the fetal compartment are more in steady state and persists even as the maternal level of BPA declines. The mid-gestational period was found to be very critical as during this time, the concentration of BPA in the fetus was relatively high; moreover, this period is also considered as critical for fetus development.
Chapter IV illustrated in-silico replica simulation of the biological system’s behaviour by reconstructing the biological emergence information and their components communication into mathematical equations. It included the development and validation of a systems biology model for ROS (reactive active oxygen species). In this first we have built our models’ ab initio, starting from the physiology of the response to oxidative stress and increasing the complexity of the network step by step. Adding every new level of complexity in a domino approach enabled us to identify design principles of ROS management. It demonstrated that both mitochondrial recovery and mitophagy may avert ROS-induced cell death. The model was validated against the in-vitro data.
Chapter V included the integrative system toxicology approach. This involves two cases 1) PBPK coupled PD with mechanistic pathway model (similar to AOP); Perfluoro octane sulfonic acid (PFOS) was selected as a case study to illustrate the ways to incorporate the use of system biological model in the field of toxicology via Pharmacodynamics coupled tissue dosimetry model(PBPK/PD). A PBPK and a mechanistic system pathway model simulated individually to get the base model. Later simulation of integrated PBPK/PD coupled mechanistic model (systems toxicology) was done. QIVIVE along with PBPK is used to evaluate the performance of the model using in-vitro data. 2) PBPK coupled PD with detailed ROS systems biology model taking the case study for the flutamide. The previously developed flutamide PBPK (chapter 2) and ROS systems biology model was used to developed integrative systems toxicology. This model is used to predict the hepatotoxicity of flutamide, illustrating the wider application of integrative systems toxicology in the field of the Human health risk assessments.
The integrative systems toxicology models have been developed; demonstrated with the example of integrated Science through the integration of multidisciplinary knowledge; and showed its wider application in predicting adverse effects on the human health. Integration of exposure, pharmacokinetics, pharmacodynamics, and systems biology under the umbrella of intergrative systems toxicology was developed.
Reconstructing mode of actions/biological behavior in an in silico replica of the system and simulation of this system has shown to be solving the complexity of the biological system. Moreover, mechanistically understanding of the system as an interconnected processes has led to development of better integrative in-silico predictive model.
