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 a (PPARa) 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 PPARa 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 PPARa-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.

Creating a Structured Adverse Outcome Pathway Knowledgebase via Ontology-Based Annotations

“…Peroxisome Proliferator Activated Receptor α (PPARα) is a ligand-activated transcription factor which belongs to the family of nuclear receptors and acts as key regulator of lipid metabolism. The linkage between the activation of PPARα and the impairment of steroidogenesis leading to effects on reproduction is supported by evidence in both rodent and human studies and described in an AOP currently under review (https://aopwiki.org/ aops/18) (46,47). A summary diagram of the annotated AOP is presented in Figure 5 (Supplementary Table 3).…”

“…In order to describe the underlying molecular process in its entirety, from the ligand-mediated activation of the transcription factor to its following translocation to the nucleus, the class 'peroxisome proliferator activated receptor signaling pathway' (GO:0035357), a subclass of 'signal transduction' (GO:0023033) was chosen in accordance with convention (4). The directionality of the Process is defined by the Action term 'increased,' as illustrated by convention ( 6) and the Cell Context term 'eukaryotic cell' (CL:0000255) was used to represent the wide range of PPARα expression (46,47).…”

“…For the KE, "Testosterone level, Reduction," the text describes the reduction of circulating testosterone in the bloodstream (46,47). As a whole, annotation of this KE combines different conventions.…”

The use of adverse outcome pathways in the safety evaluation of food additives

“…AOPs can also be used to identify mechanisms of toxicity associated with adverse outcomes found in toxicity tests, and thus help determine the relevance of the toxic effect to humans. In addition, information from AOP perturbations, such as from screenings, allows for incorporation of additional endpoints, such as induction of biotransformation enzymes, to explain liver effects (Kang et al 2018;Nepelska et al 2017). For example, when it is known that the tumorigenesis of a chemical in rodents is related to peroxisome proliferator-activated receptor alpha activation, using these data for risk assessment is questionable, since the pathway is not relevant in humans (Corton et al 2018).…”

Phthalates mixtures in bottled water in Iran: human health risk assessment using direct and indirect exposure assessment

“…Peroxisome proliferators are characterised as non-genotoxic rodent carcinogens (Roberts et al, 2000). MEHP and DEHP are peroxisome proliferators and act as an exogenous ligand of PPARs including PPAR alpha (PPARα) and PPARγ mediated gene expression resulting in hepatocarcinogenic cell proliferation (Nepelska et al, 2017;Oral et al, 2016;Hurst et al, 2003;). According to in vitro and in vivo studies, DEHP stimulated activation of PPARγ leading to the production of oxidative stress and downregulated expression of insulin receptor and GLUT4 proteins, disrupting the insulin-signalling pathway in the liver of SD rats and L02 cells (Zhang et al, Chapter 35 2017).…”