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Adverse Outcome Pathway: Peroxisome Proliferator-Activated Receptor α Activation and Reproductive Toxicity—Development and Application in Assessment of Endocrine Disruptors/Reproductive Toxicants

Abstract: 
In the process of a paradigm shift in toxicity testing, many efforts have focused on how to integrate and interpret information for biological events occurring at molecular and cellular level to be predictive of adverse effects at organism or population level to be useful, for example, for regulatory decision-making. The adverse outcome pathway (AOP) concept provides such a framework of knowledge-based safety assessment of chemicals that links mechanistic information with an apical endpoint. Here we outline an AOP that links the activation of peroxisome proliferator-activated receptor α (PPARα) to reproductive tract malformations and impaired fertility in males. The development of this AOP relies on evidence collected from rodent models and incorporates human mechanistic and epidemiological data. Interest in PPARα action as a mechanistic basis for effects on the reproductive system arises from the relationships between activation of this receptor and impairment of steroidogenesis leading to reproductive toxicity. The PPARα-initiated AOP is a first step for structuring current knowledge about mode of action (MoA), which is neither androgen receptor-mediated nor via direct aromatase inhibition. In the current form, the pathway lays a strong basis for linking an endocrine MoA with an adverse effect, a prerequisite requirement for the identification of endocrine disrupting chemicals.