You are here:
A Quantitative Adverse Outcome Pathway for Ecotoxicity: Modeling Reproductive Adversity in Fathead Minnows
Citation:
Conolly, R. A Quantitative Adverse Outcome Pathway for Ecotoxicity: Modeling Reproductive Adversity in Fathead Minnows. 3rd International Conference on Toxicity Testing Alternatives & Translational Toxicology, Nanjing, China, CHINA, July 09 - 12, 2017.
Impact/Purpose:
This abstract describes a fully quantitative version of an adverse outcome pathway (AOP). The AOP links inhibition of the enzyme CYP19A (aromatase) in the ovary of the fathead minnow (FHM) with reproductive failure and population decline. Aromatase converts testosterone into estradiol (E2). Egg production in the FHM is E2-dependent, hence the reproductive failure. The significance of having a quantitative AOP (qAOP) is that it provides a capability to describe (1) how the FHM attempts to maintain homeostasis by compensating for the aromatase inhibition and (2) the dose-response and time course of reproductive failure and population decline when compensation fails. These quantitative, predictive capabilities that are functions of the degree and duration of inhibition of aromatase distinguish the qAOP from the AOP on which it is based.
Description:
A quantitative adverse outcome pathway (qAOP) consists of interrelated computational models that together describe the mechanistic biology linking a toxicant-induced, molecular-level initiating event (MIE) with an adverse outcome at the level of individuals or populations. A qAOP can link chemical-specific, in vitro screening data describing the MIE with quantitative insights into in vivo dose-response behavior. In this paradigm, the considerable investment of resources to initially develop the qAOP is rewarded by the subsequent capability to use computational models to link high throughput screening data with quantitative predictions of in vivo toxicity. In this presentation I will describe a qAOP linking inhibition of cytochrome P450 19A aromatase (the MIE) to the adverse outcome of population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application to multiple chemicals, may be sufficient to justify the cost for some applications in regulatory decision-making. This abstract does not necessarily reflect any specific policy of the US EPA.