Abstract
Adverse outcome pathways (AOPs) are conceptual frameworks that organize and link contaminant-induced mechanistic molecular changes to adverse biological responses at the individual and population level. AOPs leverage molecular and high content mechanistic information for regulatory decision-making, but most current AOPs for hormonally active agents (HAAs) focus on nuclear receptor-mediated effects only despite the overwhelming evidence that HAAs also activate membrane receptors. Activation of membrane receptors triggers non-genomic signaling cascades often transduced by protein phosphorylation leading to phenotypic changes. We utilized label-free LC-MS/MS to identify proteins differentially phosphorylated in the brain of fathead minnows (Pimephales promelas) aqueously exposed for 30 minutes to two HAAs, 17α-ethinylestradiol (EE2), a strong estrogenic substance, and levonorgestrel (LNG), a progestin, both components of the birth control pill. EE2 promoted differential phosphorylation of proteins involved in neuronal processes such as nervous system development, synaptic transmission, and neuroprotection, while LNG induced differential phosphorylation of proteins involved in axon cargo transport and calcium ion homeostasis. EE2 and LNG caused similar enrichment of synaptic plasticity and neurogenesis. This study is the first to identify molecular changes in vivo in fish after short-term exposure and highlights transduction of rapid signaling mechanisms as targets of HAAs, in addition to nuclear receptor-mediated pathways.
Highlights
The burden of toxicity assessments for the large number of chemicals on the market or coming to market has inspired new approaches to chemical prioritization, testing and regulation, globally
Middle-out approaches start with a phenotype or key events (KE) at the organism level that is not directly connected to an molecular initiating event (MIE) or an AO but is subsequently connected by identifying the mechanisms underlying the change in the KE and linking that to a causal change leading to an AO2,3
Used modestly to assess the effects of environmental contaminants in human systems[11,12,13] and in two studies focused on zebrafish development[14,15], these methods have not translated to ecotoxicological assessment of contaminant exposure in non-mammalian species as a means to identify modes of action in target tissues or MIEs and key events in Adverse outcome pathways (AOPs)
Summary
The burden of toxicity assessments for the large number of chemicals on the market or coming to market has inspired new approaches to chemical prioritization, testing and regulation, globally. Activation of nuclear estrogen receptor alpha (ESR1) by xenoestrogens in fish is considered an MIE and such activation can initiate a series of key events including changes in expression of estrogen-responsive genes and alterations in circulating plasma sex steroids and vitellogenin. These biological responses have been further www.nature.com/scientificreports/. Probing the phosphoproteome can provide additional mechanistic information that may be used in read-across analyses of chemicals with similar (or different) actions in the brain
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