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Modeling the Retinoid System in Biology and Toxicology
Citation:
Knudsen, T. Modeling the Retinoid System in Biology and Toxicology. 11th World Congress on Alternatives and Animal Use in the Life Sciences Virtual Conference (WC11), NA, Virtual, NETHERLANDS, August 23 - September 02, 2021. https://doi.org/10.23645/epacomptox.16543212
Impact/Purpose:
This is an invited presentation in a symposium on 'Organising frameworks: KCs, MOAs and AOPs - Mutually Informative, Not Mutually Exclusive' at the 11th World Congress on Alternatives and Animal Use in the Life Sciences Virtual Conference August 2021.
Description:
Environmental chemical interactions with the retinoid signaling pathway were identified as an area for novel assays development and further prioritized to fill in existing gaps in data for regulatory evaluation of chemical hazard by several recent expert reviews. All-trans retinoic acid (ATRA) is an endogenous signal that interacts with several important pathways in tissue biology. ATRA-dependent gene expression is a molecular determinant of embryonic patterning, growth and differentiation. Genetic disruption of the retinoid pathway has adverse developmental outcomes such as phocomelia, heart and neural tube defects; however, it is not clear if these phenotypic outcomes are attributable exclusively to retinoid-related mechanisms, and currently there are currently no definitive in vivo or in vitro retinoid pathway endpoints in regulatory test guidelines. This motivates elucidation of adverse outcome pathway (AOP) frameworks for retinoid embryopathy. An OECD Detailed Review Paper (DRP 4.97) was developed to scope existing in vitro assays for potential mechanistic targets, identify model chemicals that interfere with those targets, and describe in vivo endpoints that anchor the chemical effect to an adverse response in animals. These mechanistic data and in vivo outcomes can be linked in an integrated approach for testing and assessment (IATA) to aid regulatory interpretation and decision making. Therefore, the ATRA system provides an excellent opportunity for case studies aiming to establish reliability of in vitro data and in silico models for predictive developmental toxicity, and recommendations for regulatory uptake and interpretation. Does not reflect Agency policy.
URLs/Downloads:
DOI: Modeling the Retinoid System in Biology and Toxicology
WC11_KNUDSEN_1126_ATRA_V2.PDF (PDF, NA pp, 2210.44 KB, about PDF)