Poison frogs appear to have built their chemical defenses gradually: related frogs store low to moderate levels of diet-derived alkaloids, whilst poison frogs store more and could chemically modify them.

Poison frogs are small brightly colored amphibians that live in Central and South America. As their name suggests, these frogs are highly poisonous, with toxic chemicals in their skin and bodies that are accumulated specifically to deter and neutralize their predators.

The toxins accumulated by poison frogs, known as alkaloids, are derived from their diet in the wild, which consists of specific ants, mites, millipedes, and beetles. These alkaloids are powerful neurotoxins (Allegedly, Russian opposition leader Alexei Navalny was killed using a deadly neurotoxin from poison frogs).

Poison frogs absorb and store alkaloids via a process called sequestration, and in some cases they chemically modify these poisons to further increase their toxicity. How do these ingested alkaloids enter the body and accumulate in the internal organs without the frogs poisoning themselves? An international team of researchers wondered the same thing.

“I also wonder how they are able to accumulate so many toxins from their diet,” said the study’s lead author, chemical ecologist and evolutionary biologist Adriana Moriguchi Jeckel, a Postdoctoral Researcher at the University of California, Berkeley , where she studies the ecological and evolutionary aspects of chemical defense in amphibians.

“I was also fascinated by the diversity of alkaloids, the type of toxin they accumulate, that we find in a single individual in nature. Sometimes, we find more than 40 different alkaloids in a single frog,” Dr Jeckel explained in email. “This means their mechanisms for resisting and accumulating toxins must be able to handle all these different compounds. This is not very common in sequestering organisms. In this study, we demonstrate that some of this diversity may come from their ability to modify ingested alkaloids. It is unclear whether this modification plays an ecological role in defending against predators or pathogens, but it could explain the high diversity found in the frogs. Their ability to accumulate so much toxin, coupled with their bright, conspicuous coloration, makes me wonder about their evolutionary pathway to reach their current state.”

“We have an idea of some of their strategies, but we don’t know the whole picture yet,” Dr Jeckel told me in email. “This is one of the things that inspired me to study them.”

How complex adaptive traits evolved is controversial

The evolutionary origin of complex adaptive traits has long been a controversial topic in the history of evolutionary biology. On one hand, Charles Darwin argued that complex adaptive traits evolved gradually, in accordance with the theory of natural selection, whereas a contemporary of Darwin’s, St. George Mivart alleged that natural selection could not account for the incipient stages of complex traits, thus these traits must appear suddenly. This debate eventually splintered the former friends into enemies who espoused two opposing views of evolution: gradualism versus saltationism.

According to the argument, gradualists declare that complex traits arise through the continuous accumulation of tiny changes, each subjected to natural selection ( ref ). In contrast, a saltational view of evolution proposes that complex traits arise through sudden, discontinuous leaps from one optimum to another, and that significant mutational leaps lead to the sudden emergence of entirely new traits ( ref ).

Sequestering large amounts of a variety of different toxins is one example of a complex adaptive trait. Today we know that complex traits are those that are under the control of multiple genes. For example, in humans, complex traits include height, intelligence and cognitive function, just to name a few.

Poison frog toxins provide an example of adaptive complex traits

How can we resolve this debate over the origin and evolution of complex traits? Poison frogs provide a useful model system because they can sequester and modify a variety of alkaloid toxins from the variety of invertebrates that they eat, thus providing an opportunity to explore the emergence of these complex traits.

To explore this question, Dr Jeckel and collaborators conducted two laboratory experiments. In these experiments, they carefully controlled the food accessible to the frogs and examined how their ability to accumulate alkaloids differed.

“We selected one tree frog ( Dryophytes cinereus ) from the family Hylidae, which is phylogenetically distant from poison frogs and was not expected to sequester alkaloids,” explained Dr Jeckel. “We also selected one species ( Allobates femoralis ) from the Aromobatidae family, a sister family of poison frogs. Finally, we selected several poison frogs from the family Dendrobatidae. We fed them different alkaloids and quantified the total amount sequestered in their skin.”

“Until very recently, the sister groups of these poison frogs were thought to lack the ability to sequester alkaloids. This led to our central question: How did this complex ability evolve?” Dr Jeckel pointed out.

In experiments 1 and 3, Dr Jeckel and collaborators used a micropipette to feed solutions containing known amounts of alkaloid toxins to the frogs. This allowed the researchers to track how much of the alkaloids that the frogs ingested daily reached their skin, as well as their vital organs.

“In the second experiment, we used the first known method of feeding alkaloids to poison frogs, which involves sprinkling alkaloids on their food, fruit flies,” said the study’s senior author, chemical ecologist Ralph Saporito, a professor at John Carroll University .

“This method does not allow for exact quantification of alkaloid accumulation, but it best approximates what naturally happens: ingesting an arthropod with the alkaloid,” Professor Saporito explained. “Both methods enabled us to draw conclusions about the sequestration and modification of alkaloids.”

As the result of their experiments, Dr Jeckel, Professor Saporito and collaborators found that — surprisingly — the non-toxic frogs actually stored small amounts of alkaloids, whereas the frogs with a medium toxicity stored more, and poison frogs stored high levels of toxins.

“In the first experiment, in which alkaloid accumulation was compared between species from different families, we observed differences of orders of magnitude in alkaloid accumulation,” Dr Jeckel explained. “For example, the cobalt poison frog, Dendrobates tinctorius, and the splash-backed poison frog, Adelphobates galactonotus (Dendrobatidae), accumulated at least 10 times more alkaloids in their skin than the dendrobatoid, the brilliant-thighed poison frog, Allobates femoralis (Aromobatidae), which in turn accumulated 10 times more than the distantly related American green tree frog, Dryophytes cinereus (Hylidae).”

These results suggest that alkaloid sequestration evolved did not appear suddenly in new frog species but instead, it evolved gradually, with intermediate phenotypes representing transitional stages between non-sequestering species and the active sequestration and modification observed in some poison frogs.

Given current understanding of alkaloid transport and metabolism, these findings suggest possible mechanisms that enabled the gradual adaptation of poison frogs to evolve from alkaloid resistance to active sequestration and modification.

Evolutionary steps to becoming highly toxic

Living organisms must undergo a number of evolutionary adaptations before they can sequester alkaloids from the food they ingest. First, they must become resistant to the toxins they ingest, so they don’t poison themselves. Additionally, they must develop a mechanism that allows them to transport toxins from their digestive tract to the skin and one that prevents their body from metabolizing (i.e., detoxifying) toxic compounds.

“There must have been several evolutionary steps to transition from a non-sequestering phenotype to a sequestering one,” Dr Jeckel explained.

“[T]wo findings have changed our perspective on sequestration in poison frogs. Firstly, sister groups previously thought to be unable to sequester alkaloids were found to possess low levels in their skin. Secondly, studies showed that poison frogs can modify a wider variety of dietary-derived alkaloids into different chemical forms than previously thought.”

These observations suggest that sequestration abilities did not suddenly appear in poison frogs. Instead, sequestration appears to have emerged gradually within the larger animal family to which poison frogs belong. Further, the method of sequestration appears to be unique to each frog species.

“Even among sequestering species, the way they handle toxins also appears to differ,” Dr Jeckel said. “By modifying one toxin into another, these frogs are actively increasing the chemical diversity of their skin, which might have significant ecological importance for their survival against predators and protection from pathogens.”

Although this study is an important step forward in the study of the evolution of poison frogs, there are still many mysteries that remain unresolved. For example, scientists have found more than 800 toxic compounds in poison frogs, but fewer than 70 are well understood. So at this point, tracking down the sources of these toxins and deciphering the chemical biosynthesis that gives rise to them could provide important insights into how frogs evolved resistance to them.

“Our paper establishes a foundation for understanding alkaloid sequestration and resistance mechanisms in poison frogs,” Dr Jeckel said. “We have shown that closely related species may have an intermediate form of the sequestration mechanism, making them a promising group for studying these mechanisms alongside sequestering species. Additionally, we have demonstrated that the ability to modify alkaloids is unique to sequestering species and may represent an important step in the evolution of sequestration.”

These new insights could soon inspire further research focusing on the development of sequestration mechanisms, both in frogs and other toxic animals, including poisonous insects, reptiles, and birds. As part of their next studies, the team plans to investigate the molecular and physiological changes that underlie the evolution of alkaloid sequestration in poison frogs.

“Many complex adaptations are necessary to sequester alkaloids,” Dr Jeckel summarized. “We now aim to understand these changes at the molecular and physiological level. From an ecological perspective, we also want to understand the relevance, if any, of poison frogs modifying alkaloids. By modifying alkaloids, they increase the diversity of toxins in their skin, which may be important for defense against predators and pathogens.”

Adriana M. Jeckel, Sarah K. Saporito, Marta M. Antoniazzi, Carlos Jared, Kunihiro Matsumura, Keisuke Nishikawa, Yoshiki Morimoto, Taran Grant and Ralph A. Saporito (2026). Experimental evidence supports gradual evolution of alkaloid sequestration in poison frogs , Proceedings of the Royal Society B: Biological Sciences 293 (2067):20253144 | doi: 10.1098/rspb.2025.3144

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