Matching molecular initiating event and key event data.
2016 Note: ACSL5, acyl-CoA synthetase long-chain family member 5; BPS, bisphenol S; EC50, half-maximal effective concentration; ER, estrogen receptor; ERRy; estrogen-related receptor gamma; FABPs, fatty acids binding proteins; HSL, hormone-sensitive lipase; KE, key event; MIE, molecular initiating event.
Using the available literature, AOP-helpFinder can automatically find, extract, and score links between chemical substances (i.e., stressors) and diverse biological elements, i.e., molecular initiating events (MIEs), KEs, and AOs, which are the components of AOPs (Villeneuve et al.
In the same way as pushing on a single domino can lead to exotic patterns, a chemical-receptor interaction can act as a "Molecular Initiating Event
" that ultimately produces a cascade of biological responses.
Adverse outcome pathways (AOPs) begin with a molecular interaction serving as a molecular initiating event (MIE), leading to a series of key events and eventually to an adverse outcome at the organismal level for human health, and at the population level for ecotoxicology assessments.
Estrogen receptor (ER) binding and activation [i.e., the molecular initiating event (MIE)] can be linked to several related key events from EDSP Tier 1 and Tier 2 assays, leading to an adverse outcome (e.g., altered development).
EDSP Tier 1 and Tier 2 test assays mapped to an ecotoxicological adverse outcome pathway (AOP) for an estrogen receptor (ER) agonist in male fish including a molecular initiating event (MIE) of receptor binding and related key events measured in Tier 1 and Tier 2 assays and terminating in an adverse outcome represented by declines in population size and by altered sex composition.
The notion of the cell-level toxicity pathways described in the NRC report (2007) has already been extended to the broader concept of adverse outcome pathways (AOPs), thereby addressing the sequence of changes between the molecular initiating event (e.g., a chemical binds to a cell receptor) and adverse outcomes at the molecular, cellular, organ, organism, and population levels.
The adverse outcome pathway (AOP) concept links exposure, via chemical structure (or structures), the molecular initiating event, and key events, to an adverse outcome.
The simplest is at the molecular initiating event level where sequences or structures of proteins can be compared.
Extrapolation at the molecular initiating event level facilitates prediction of potential adverse effects.
QSAR Modeling of ToxCast Assays Relevant to the Molecular Initiating Events
of AOPs Leading to Hepatic Steatosis.