1 Introduction to Animal Toxins

1.1 What Are Toxins?

Toxins are molecules which are synthesized by living organisms and used to parasitize or to predate on other creatures or to avoid being attacked by predators or parasites. Poisonous animals make use of one or several toxic compounds that they secrete onto the body surface (skin, feathers, fur) or accumulate internally in body tissues to repel, to harm or to kill predators or to avoid being colonized by microorganisms. In some cases, parent animals provide protection to their young by impregnating eggs or newborns with poisonous substances.

Venoms are generally mixtures of several substances produced in specialized glands and applied to target organisms by special applicators like stings or fangs. They may be used by animals as means to efficiently obtain prey or as chemical weapons for defense against attackers. In predatory animals, venoms are used to immediately immobilize or kill prey which requires that they cause rapid onsets of their paralyzing effects. Thus, venoms used by predators mostly target neuronal or muscle cell systems with the aim of interrupting signal transmission from motor neurons to muscle cells and impairing voluntary motor functions in the target organism.

The scientific field studying the generation, the application, the molecular interactions with endogenous targets, the metabolism and excretion or elimination of natural poisons, venoms or related molecules is called 'toxinology'. It is a subdiscipline of 'toxicology'.

The extent to which toxins harm their target organisms depend on

• the kind of toxin,

• the amount of toxin,

• the pathway of application to or introduction into the target organism, e.g.,

  • topical - superficial application to parts of the body surface

  • per os or peroral (p.o.) - through the mouth

  • intraperitoneal (i.p.) - injection through the peritoneum into the body cavity

  • intramuscular (i.m.) - injection into the body wall muscle

  • intravenous (i.v.) - injection into the blood stream

  • subcutaneous (s.c.) - injection under the skin into the subcutis

• whether the toxin is acutely or chronically applied,

• the sensitivity of the target organism against the toxin,

• the metabolism of the toxin within the target organism, or

• the rate of elimination of the toxin from the target organism.

This illustrates that the toxin character of a given substance is relative and depends on many variables. This has been recognized very early in history, e.g., by Famoso Doctor Paracelsus (Philippus Theophrastus Aureolus Bombastus von Hohenheim, 1493-1541) who is famous for his proverbial phrase: 'Alle Ding' sind Gift und nichts ohn' Gift; allein die Dosis macht, das ein Ding' kein Gift ist' (everything is a poison and nothing is no poison; just the dose is relevant for its toxicity).

Also, the administration route may be relevant whether a substance acts as a toxin or not: A protein toxin that may be highly toxic when injected into an animal may be completely harmless if ingested because it is denatured by the acidic environment in the stomach and readily digested by proteases in the intestines.

The scientific discipline dealing with questions on the uptake rates, metabolism, and elimination of toxins in or from target organisms is called 'toxicokinetics'. The mechanism of action of a toxin within a target organism is studied in 'toxicodynamics'. The term 'toxicography' describes studies of complex effects of toxins on target organisms and the reasoning about potential antidotes or therapies.

In this book, we focus on biogenic substances used by animals which are directed against other animals or humans. However, antimicrobial compounds that are generated and used by animals to combat potential pathogenic microorganisms will also be considered.

1.2 Organisms as Sources for Toxic Compounds

Animals that are able to produce their own toxins display 'primary toxicity'. 'Secondary toxicity', however, is a feature of animals which are not able to originally generate their own toxins but acquire their toxins or at least precursors of such toxins from food organisms or from commensal or symbiontic microorganisms. Evolutionary adaptations in animal species with secondary toxicity to tolerate their own toxins in the body are common. An interesting example is the impregnation of tissues of inner organs in Indo-Pacific puffer fish (Tetraodontidae) of the genus Takifugu with tetrodotoxin (see Section 2.9.7), a toxin that is originally produced by bacteria (Aeromonas, Vibrio) [10, 13]. Tetrodotoxin is a highly effective blocker of voltage-gated sodium channels in animals and inhibits the generation of action potentials in neurons and skeletal muscle cells resulting in paralysis. Mutations in one of the subunits of the voltage-gated sodium channel in Takifugu which resulted in the exchange of just a few amino acids in this protein rendered the channel tetrodotoxin-resistant in these fishes [14]. Another example of evolutionary development of resistance against specific alkaloid toxins of food organisms are the poison frogs of Central and South America (see Section 3.2.12). In these animals, mutations in the NaV1.4 voltage-gated sodium channel that are conserved among the different species of frogs in the genus Dendrobates are associated with alkaloid toxin resistance [18]. Being resistant against these toxins but making the own body toxic for other organisms protects these animals from becoming victims of predators. Caterpillars of the monarch butterfly (Danaus plexippus) (see Section 3.2.9) tolerate high concentrations of cardenolides in their bodies because the a-subunit of the Na+/K+-ATPase carries a mutation (N122H, asparagine to histidine at amino acid position 122) which renders the enzyme insensitive to such steroid glycosides which, in turn, harm other organisms trying to feed on these caterpillars or the adult butterflies [7, 9].

Some animals store their toxins in specialized gland reservoirs and mobilize these compounds only to the external space. This is the case in many snakes where the toxins are contained in specialized salivary glands in the upper jaws [3, 8] and released through ducts connected to teeth that work as injection needles. Honeybees, e.g., Apis mellifera, carry their toxins in venom glands and associated storage compartments while all other tissues of such animals are entirely free of any toxic material. Such a separation of toxin compartments from other tissues in the body (sequestration) avoids being poisoned by the own toxins.

Differences in toxin profiles between individuals of the same species are common features in animals [17]. Temporal or regional differences in toxin content of animals have been observed in primarily as well as in secondarily toxic animals. Toxin profiles may also change during ontogenic development so that juveniles may express toxin compositions that differ in quality or quantity from those expressed in adults [12]. Venoms of honeybee workers vary between summer and winter and are different from that of queens [1]. Juveniles of rattlesnakes (see Section 3.2.13) may express different compositions of toxins than adult animals from the same geographical region. On the other hand, adult rattle snakes from different locations may produce venoms with different toxin compositions [6]. Similar findings have been made for the venom compositions of regional populations of the monocled cobra, Naja kaouthia [15]. Some of these differences are based on genetic differences (local adaptation) between subpopulations [5]. The marine box jellyfishes from Northern Australia (Chironex fleckeri) (see Section 3.2.2) show geographical differences in venom composition as well but it remains unclear whether these differences are due to genetic or environmental factors [16].

Especially secondarily toxic animals differ in their toxin composition depending on environmental factors. In some cases, the differences result from interaction of individuals with different types of toxin-producing microorganisms; in other cases, toxin profiles depend on the choice of food organisms. Secondary toxicity may fade away if animals are reared without access to toxin-producing microorganisms. This is the case with crust anemones (Palythoa sp., Cnidaria) in the Pacific Ocean which carry the highly toxic palytoxin (see Section 2.3.7) only when toxin-producing dinoflagellates, Ostreopsis sp., are present in the surrounding water [2].

The tissue distribution of toxins in animals that impregnate their tissues with toxic compounds to deter predators is more generalized. Certain...