The Diverse Mechanisms that Animals Use to Resist Toxins

Abstract

Biological toxins are entrenched within ecosystems. Thus, animals are often exposed to such toxins, and how they adapt can be a key determinant of their evolutionary trajectories. In this review, we provide an overview of the diversity of toxin resistance mechanisms, with a focus on animals that sequester toxins from their diet and their natural predators and parasites. We propose a structured framework in which to study toxin resistance by recategorizing and reorganizing known mechanisms into avoidance, metabolism, and target categories. Then, using this framework, we review evidence regarding how animals resist four widely studied compounds: tetrodotoxin, batrachotoxin, cardiac glycosides, and pyrrolizidine alkaloids. Based on the available data, we conclude that toxin resistance and sequestration are interrelated from both ecological and evolutionary perspectives. To conclude, we highlight open questions regarding toxin resistance and review its importance as a field. En los ecosistemas las toxinas de origen biológico son componentes intrínsecos. Por esta razón, los animales se ven expuestos frecuenciamente a dichas toxinas y la forma en que se adaptan puede ser un factor que determina su trayectoria evolutiva. Esta revisión ofrece una visión general de la diversidad de mecanismos de resistencia a toxinas, centrándose en animales que secuestran toxinas de su dieta y en sus depredadores y parásitos naturales. En este texto se propone un marco estructural para estudiar la resistencia a toxinas mediante la recategorización y reorganización de mecanismos conocidos en categorías de: evación, metabolismo y moléculas diana. A continuación, utilizando este marco, revisamos la literatura científica en busca de evidencia sobre cómo los animales resisten a cuatro compuestos ampliamente estudiados: tetrodotoxina, batracotoxina, glucósidos cardíacos y alcaloides de pirrolizidina. A partir de los datos disponibles, llegamos a la conclusión de que la resistencia y la retención de toxinas están interrelacionadas tanto desde el punto de vista ecológico como evolutivo. Por último, destacamos algunas preguntas abiertas en torno a la resistencia a las toxinas y resaltamos su importancia como campo de estudio en el futuro. Expected final online publication date for the Annual Review of Ecology, Evolution, and Systematics, Volume 54 is November 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Toxic to the touch: The makings of lethal mantles in pitohui birds and poison dart frogs

“…How do these birds withstand high levels of BTX in their bodies? Successful sequestration strategies require careful handling of toxins after ingestion and xenobiotic detoxification mechanisms play key roles in these (Tarvin et al., 2023). Common mechanisms involve toxin metabolism by the animal or its microbiome, target‐site insensitivity, or the existence of alternative targets of toxins in the form of “toxin sponges” (Tarvin et al., 2023).…”

“…Successful sequestration strategies require careful handling of toxins after ingestion and xenobiotic detoxification mechanisms play key roles in these (Tarvin et al., 2023). Common mechanisms involve toxin metabolism by the animal or its microbiome, target‐site insensitivity, or the existence of alternative targets of toxins in the form of “toxin sponges” (Tarvin et al., 2023). In the case of BTX, previous research on Phyllobates poison dart frogs identified amino acid substitutions in the toxin‐binding site of the voltage‐gated sodium channel Nav1.4.…”

“…In the case of BTX, previous research on Phyllobates poison dart frogs identified amino acid substitutions in the toxin‐binding site of the voltage‐gated sodium channel Nav1.4. Molecular docking analyses and functional genetic experiments in human cell lines suggest that these substitutions may confer target‐site insensitivity in vivo (Márquez et al., 2018; Tarvin et al., 2023, and references therein). However, recent work indicates that, rather than on target‐site insensitivity, Phyllobates frogs may rely more on a “toxin sponge” in the form of a protein called saxiphilin to prevent BTX autotoxicity (Abderemane‐Ali et al., 2021).…”

“…Although unknown mechanisms of BTX resistance might exist, these observations suggest that pitohuis and other toxic birds may rely more on target‐site insensitivity than on a “toxin sponge” to prevent BTX autotoxicity. In light of the conflicting findings between studies on the relative importance of different BTX resistance mechanisms in toxin‐coopting birds and frogs, future work could focus on gathering in vivo functional genetic data to resolve discrepancies in the literature (Tarvin et al., 2023, and references therein). Ongoing developments in CRISPR/Cas9 technology may enable such tests of the molecular mechanisms that underlie BTX autoresistance in relatively realistic bird and frog model systems.…”

“…In the case of BTX, previous research on Phyllobates poison dart frogs identified amino acid substitutions in the toxin-binding site of the voltage-gated sodium channel Nav1.4. Molecular docking analyses and functional genetic experiments in human cell lines suggest that these substitutions may confer target-site insensitivity in vivo (Márquez et al, 2018;Tarvin et al, 2023, and…”