Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians

Abstract

In the present review, we synthesize information on the mechanisms of chronic copper (Cu) toxicity using an adverse outcome pathway framework and identify three primary pathways for chronic Cu toxicity: disruption of sodium homeostasis, effects on bioenergetics, and oxidative stress. Unlike acute Cu toxicity, disruption of sodium homeostasis is not a driving mechanism of chronic toxicity, but compensatory responses in this pathway contribute to effects on organism bioenergetics. Effects on bioenergetics clearly contribute to chronic Cu toxicity with impacts at multiple lower levels of biological organization. However, quantitatively translating these impacts into effects on apical endpoints such as growth, amphibian metamorphosis, and reproduction remains elusive and requires further study. Copper-induced oxidative stress occurs in most tissues of aquatic vertebrates and is clearly a significant driver of chronic Cu toxicity. Although antioxidant responses and capacities differ among tissues, there is no clear indication that specific tissues are more sensitive than others to oxidative stress. Oxidative stress leads to increased apoptosis and cellular damage in multiple tissues, including some that contribute to bioenergetic effects. This also includes oxidative damage to tissues involved in neuroendocrine axes and this damage likely alters the normal function of these tissues. Importantly, Cu-induced changes in hormone concentrations and gene expression in endocrine-mediated pathways such as reproductive steroidogenesis and amphibian metamorphosis are likely the result of oxidative stress-induced tissue damage and not endocrine disruption. Overall, we conclude that oxidative stress is likely the primary driver of chronic Cu toxicity in aquatic vertebrates, with bioenergetic effects and compensatory response to disruption of sodium homeostasis contributing to some degree to observed effects on apical endpoints. Environ Toxicol Chem 2022;41:2911-2927. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Keywords: Adverse outcome pathway; copper; endocrine disruption; mode of action; oxidative stress.

Figure 1

Adverse outcome pathway for effects of Cu on Na⁺ homeostasis in freshwater vertebrates. Solid lines indicate relationships that are well supported in the literature. Dashed lines indicate hypothesized relationships or relationships supported by limited or conflicting data.

Figure 2

Adverse outcome pathway for the effects of Cu‐induced oxidative stress on freshwater vertebrates. Solid lines indicate relationships that are well supported in the literature. Dashed lines indicate hypothesized relationships or relationships supported by limited or conflicting data. ROS = reactive oxygen species; HPG = hypothalamic–pituitary–gonadal.

Figure 3

Adverse outcome pathway for effects of Cu on bioenergetics in freshwater vertebrates. Solid lines indicate relationships that are well supported in the literature. Dashed lines indicate hypothesized relationships or relationships supported by limited or conflicting data. *Note, in this figure pathways are initiated by key events. Molecular initiating events are described in other figures or are unkown. ROS = reactive oxygen species; ER = endoplasmic reticulum.

Figure 4

High‐level conceptual model of adverse outcome pathways for chronic Cu exposure to vertebrates integrating the more detailed adverse outcome pathways presented in Figures 1 through 3. Solid lines indicate relationships that are well supported in the literature. Dashed lines indicate hypothesized relationships or relationships supported by limited or conflicting data. Oxidative stress and tissue damage are shown in bold to highlight the dominant pathway for chronic Cu toxicity. Change in endocrine function is due to direct tissue damage from oxidative stress and is not endocrine disruption.