Chapter 3

Arthropod Toxins and Venoms

Justin O. Schmidt
Southwestern Biological Institute, Tucson, AZ, United States; Department of Entomology, University of Arizona, Tucson, AZ, United States

Chemicals play many important roles in the lives of insects, forming the sting in scorpions (see Fig. 23.7); and the
arachnids, and other arthropods. Chemicals serve a number modified chelicerae and venom glands of spiders (see
of functions, including communication, both within and Fig. 25.2).
between or among species; sex attraction and mating; ag- Table 3.1 provides an overview of the more important
gregation behavior; finding and capturing prey or other insects and arachnids of medical and veterinary importance
food; defending themselves, or their offspring, nests, and that produce toxins and venoms. They include the insect
hives, against predators and other natural enemies; alerting orders Hymenoptera, Coleoptera, and Lepidoptera and the
members of their species to perceived threats by alarm arachnid orders Scorpiones and Araneae. Also included in
pheromones; marking trails with trail pheromones; and a the table is information on the geographic occurrence of the
variety of other behaviors, particularly among social listed taxa, the toxic compounds they produce, and the
insects. respective effects on vertebrates.
From a medical-veterinary perspective, the encounters
between arthropods and humans or domestic animals
typically involve chemicals used for offense (e.g., subduing
and killing prey) and defense (e.g., biting or stinging
behavior when disturbed or threatened). The chemicals
involved are extremely diverse in their structures and
modes of action, causing a wide range of adverse effects,
depending on the species involved. The term toxin is
applied to any specific chemical compound or molecule
that causes harm to an organism on contact or when
ingested. The term venom refers to a toxin or, more typi-
cally, a mixture of one or more toxins and other chemicals,
involving specialized morphological structures for inject-
ing, spraying, or otherwise directing them to a target. The
injection of venom by such specialized structures is called
envenomation.
Examples of such structures are the modified female
reproductive organs and associated muscles and glands
forming the sting apparatus in bees, wasps, and ants FIGURE 3.1 Venom sac and sting apparatus of the red imported fire ant
(Figs. 3.1 and 3.2; see also Figs. 22.1, 22.3, and 22.4); the (Formicidae, Solenopsis invicta), dissected from a worker ant. Venom is
specialized setae and spines of urticating caterpillars that injected at the sting site via a channel formed by the pair of barbed lancets,
at right, which penetrate the skin when an ant stings; the smaller, accessory
facilitate toxins penetrating the skin on contact (see
sac is Dufour’s gland, which produces a trail pheromone. Photograph by
Figs. 21.4 and 21.5); the terminal abdominal segment Justin O. Schmidt.

Medical and Veterinary Entomology. https://doi.org/10.1016/B978-0-12-814043-7.00003-0 23

Copyright © 2019 Elsevier Inc. All rights reserved.
24 Medical and Veterinary Entomology
(A)
(B)
FIGURE 3.2 A honey bee (Apidae, Apis mellifera), worker. (A) The bee
has just stung a victim, leaving the barbed lancets of the sting apparatus
embedded in the skin, after having been torn from the bee’s abdomen. (B)
Close-up of the pair of barbed lancets, which slide along one another as
they penetrate the skin. Photographs by Justin O. Schmidt.
NATURE OF TOXINS AND VENOMS AND
THEIR EFFECTS
The chemical structures of toxins and venoms vary from
small, simple acids (Fig. 3.3) and intermediate-sized
compounds (Figs. 3.4 and 3.5) to large, complex mole-
cules (Figs. 3.6e3.8) involving up to 35 or more amino
acids. The following examples illustrate the diversity and
complexity of chemical structures among toxins and
venoms found in insects and arachnids: formic acid of
formicine ants and some beetles (Fig. 3.3); acetic acid
sprayed as a defensive secretion by the whip-scorpion, or
vinegaroon, Mastigoproctus giganteus (Fig. 3.3);
cantharidin of certain blister beetles, such as
Epicauta spp. (Fig. 3.4); pederin of certain rove beetles,
such as Paederus spp. (Fig. 3.4); solenopsin in the
venom of fire ants (Fig. 3.5) and poneratoxin of the
bullet ant Paraponera clavata (Fig. 3.6); melittin of
honey bees, such as Apis mellifera (Fig. 3.6); scyllatoxin
and agitoxin in venom of the deathstalker scorpion,
Leirurus quinquestriatus (Fig. 3.7); and atracotoxin in
venom of the Sydney funnelweb spider, Atrax robustus
(Fig. 3.8).
Toxins are typically fat soluble and water repellent
(hydrophobic), which aid toxins in penetrating the integu-
ment (e.g., waxy outer layer of the cuticle in arthropods and
vertebrate skin) on contact. Venoms, on the other hand,
tend to be more water soluble. They often consist of
complex mixtures with other chemicals that facilitate the
spread and effectiveness of the toxic components once they
penetrate the integument to enter the more aqueous envi-
ronment within.
The more potent components of arthropod venoms are
typically proteins in the form of peptides and polypeptides,
consisting of one or more chains of amino-acid residues
(Figs. 3.6e3.8). A dazzling variety of venom proteins are
known: enzymes such as phospholipases, hyaluronidases,
phosphatases, esterases, and proteases, in addition to spe-
cific enzymes acting as neurotoxins. These proteins are
responsible for much of the damage, and sometimes
lethality, that can occur. Venom peptides include hemoly-
sins, such as melittin (Fig. 3.6), that destroy blood cells;
kinins, which cause pain and cardiovascular effects; and
various neurotoxins. Venoms also can contain cocktails of
biogenic amines, including histamine, serotonin, acetyl-
choline, and epinephrine. These components can cause
swelling and other reactions, and sometimes the pain, at
sting sites. Neurotoxins are especially important in the
venom of dangerous scorpions and spiders. Other toxic
compounds are cardiotoxins of milkweed butterflies and
certain beetles and quinones and hydroquinones of
millipedes.
A number of toxins cause immediate, and often intense,
pain. This serves as a powerful deterrent to predators and
other perceived threats, including humans and both do-
mestic and wild animals. Although pain is commonly
associated with localized swelling or erythema at the bite
site, it also can be inflicted without causing other apparent
harm. An extreme example of pain acting alone is the ta-
rantula hawk Pepsis chrysothemis, a spider wasp (Pompi-
lidae) that stings and paralyzes tarantulas as food for its
developing offspring (Fig. 3.9). Its sting is excruciatingly
painful, yet 2,000 stings would be required to kill a 110-lb
(50-kg) person (Schmidt, 2004).
Although fatalities represent only a small percentage of
cases, people and domestic animals can succumb to lethal
TABLE 3.1 Important Toxic and Venomous Insects and Arachnids
Toxic Components and Their Effects on Toxin or
Common Names Scientific Names (Species and Family) Major Geographic Distribution Vertebrates Venom
INSECTS
Hymenoptera
Honey bees Apis mellifera; other Apis spp. (Apidae) Worldwide Melittin: inhibits protein kinases and ion Venom
transport across cell membranes; increases
permeability of cell membranes and cell lysis;
cardiotoxic Phospholipase A2: lung congestion
and allergic reactions
Yellowjackets and Vespula, Dolichovespula, Vespa spp. (Vespidae) Northern Hemisphere (excluding Kinins: hemolysis and pain Venom
hornets Sub-Saharan Africa) Phospholipase A1: allergic reactions.
Mastoparans destroy mast cells
Paper wasps Polistes spp. (Vespidae) Worldwide Similar to yellowjackets and hornets Venom
Polybine and Old Polybia occidentalis, Ropalidia marginata, Mostly tropics, worldwide Similar to yellowjackets and hornets Venom
World paper wasps and others (Vespidae)
Fire ants Solenopsis invicta and other Solenopsis spp. New World Tropics and Subtropics; Piperidine alkaloids (e.g., Solenopsin): inhibit Venom
(Formicidae) invasive to many other areas angiogenesis via kinase signaling pathway;
cytotoxicity, hemolysis, necrosis, and pain
Bulldog ants Myrmecia pilosula, M. gulosa, and other Australia, Tasmania Pilosulin: enzyme that can cause severe allergic Venom
Myrmecia spp. (Formicidae) reactions, including anaphylaxis
Bullet ant Paraponera clavata (Formicidae) New World Tropics; moist regions Poneratoxin: neurotoxic peptide; acts on Venom
voltage-gated Naþ channels in skeletal muscle
fibers, causing paralysis; extreme pain
Harvester ants Pogonomyrmex maricopa; many other New World; especially warm, arid Phospholipases and other enzymes Venom
Pogonomyrmex spp. (Formicidae) regions (e.g., Barbatolysin); extreme pain and potential
anaphylaxis
Coleoptera
Blister beetles Epicauta spp. (Meloidae) Worldwide Cantharidin: blistering agent; monoterpene that Toxin
causes release of proteases and other enzymes
that destroy adhesion of cells; severe damage to
gastrointestinal and urinary tracts if ingested
(e.g., horses)
Rove beetles Paederus spp. (Staphylinidae) Worldwide; warm, moist regions Pederin: an amide produced by Pseudomonas Toxin
endosymbionts; prevents cell division; inhibits
protein and DNA synthesis, causing vesicating
dermatitis
Lepidoptera
Lonomia caterpillars Lonomia achelous and L. obliqua (Saturniidae) South America Proteolytic enzymes: break down fibrinogen in Venom
blood causing hemorrhaging; can lead to heart
and kidney failure

Continued
TABLE 3.1 Important Toxic and Venomous Insects and Arachnidsdcont’d

Toxic Components and Their Effects on Toxin or

Common Names Scientific Names (Species and Family) Major Geographic Distribution Vertebrates Venom
Processionary Thaumetopoea processionea, T. wilkinsoni, and Europe, Asia, Africa, and Australian Thaumetopoein: an urticating toxin; causes Venom
caterpillars other Thaumetopea spp. (Thaumetopoeidae) region dermatitis, rash, conjunctivitis; if inhaled,
pharyngitis, respiratory distress, and asthma
Puss moth Megalopyge opercularis and other Megalopyge North America and South America Protein toxins: cause local and intense radiating Venom
caterpillars spp. (Megalopygidae) pain; edema, welts, pruritus, erythema, and rash
ARACHNIDS
Scorpiones
Brazilian yellow Tityus serrulatus (Buthidae) Central America and South America Tityus serrulatus toxin 1 (Ts1): peptide Venom
scorpion neurotoxin acting on voltage-gated sodium
channels; causes massive release of
neurotransmitters affecting nervous and
muscular systems throughout body
Bark scorpion Centruroides sculpturatus (Buthidae) Southwestern US and northwestern Centruroides toxins: peptide neurotoxins acting Venom
Mexico on Naþ channels
Deathstalker Leiurus quinquestriatus (Buthidae) North Africa and Middle East Scyllatoxin: neurotoxin that blocks Venom
scorpion Ca2þ-activated Kþ channels; can severely
affect pulmonary and cardiac systems
Agitoxin: blocks Kþ channels
Fattail scorpion Androctonus australis (Buthidae) North Africa and Middle East to India Androctonus toxins: peptide neurotoxins acting Venom
on Naþ channels
Araneae
Black widow spiders Latrodectus mactans and other Latrodectus spp. Worldwide a-Latrotoxin: neurotoxin that acts on pre- Venom
(Theridiidae) synaptic nerve terminals, causing massive
release and depletion of neurotransmitters; local
pain, muscle cramps; paralysis of diaphragm
and potential asphyxiation
Brazilian wandering Phoneutria nigriventer (Ctenidae) South America Phoneutria toxins: peptide neurotoxins acting on Venom
spider Naþ channels
Sydney funnelweb Atrax robustus (Hexathelidae) Australia d-Atracotoxin (robustoxin): neurotoxin that Venom
spider causes repetitive firing and prolonged action
potentials; continuous release of acetylcholine;
can lead to circulatory and respiratory failure
Recluse spiders Loxosceles reclusa, L. laeta, and other Worldwide Sphingomyelinase D: enzyme that breaks down Venom
Loxosceles spp. (Sicariidae) sphingomyelin in plasma membranes, causing
cell destruction, inflammation, and necrotic skin
lesions

For the Larger Taxonomic Groups, Only the More Important Species and Representative Taxa are Noted (Ca, Calcium; K, Potassium; Na, Sodium).

FIGURE 3.3 Two structurally simple toxins found in arthropods: formic
acid, typical of some biting ants; and acetic acid, a defensive compound in
arachnids called vinegaroons (Thelyphonida; e.g., whip-scorpion, Masti-
goproctus giganteus).
FIGURE 3.4 Toxins that serve as defensive agents in beetles; both can
cause dermatitis on contact with skin and injury to the gastrointestinal tract
when ingested: cantharidin, in the hemolymph of blister beetles (Meloidae,
e.g., Epicauta spp.) and pederin, in the hemolymph of certain rove beetles
(Staphylinidae, e.g., Paederus spp.).
envenomation by various biting and stinging arthropods
such as honey bees (Schmidt, 2018), Asian hornets (Liu
et al., 2016), scorpions (Chippaux and Goyffon, 2008), and
spiders (Vetter and Isbister, 2008). Livestock, especially
FIGURE 3.5 Solenopsin, a piperidine alkaloid and the primary toxin in venom of fire ants (Formicidae, Solenopsis spp.).
Arthropod Toxins and Venoms Chapter | 3 27
FIGURE 3.6 Two peptide toxins in hymenopteran insects: melittin in
honey bees (Apidae, e.g., Apis mellifera) with 26 amino acids, and
poneratoxin, a 25-residue peptide neurotoxin in bullet ants (Formicidae,
e.g., Paraponera clavata). Images from RCSB PDB (www.rcsb.org):
melittin, PDB ID 2MLT, Gribskov, M., Wesson, L., Eisenberg, D. (2018)
[“To Be Published”]; poneratoxin, PDB ID 1G92, Szolajska, E., Poz-
nanski, J., Ferber, M.L., Michalik, J., Gout, E., Fender, P., Bailly, I.,
Dublet, B., Chroboczek (2004) Eur. J. Biochem. 271: 2127e2136.
horses, can die from ingesting toxic blister beetles (Cap-
inera et al., 1985).
Allergic reactions to stings represent a particular
concern to sensitized individuals, with such reactions to
insect stings occurring in approximately 1%e4% of human
populations. Responses can include dermal rashes and
edema at a distance from the sting site; difficulty breathing
caused by swelling of the throat and respiratory passages;
and a severe drop in blood pressure, followed by faintness
28 Medical and Veterinary Entomology
FIGURE 3.7 Two neurotoxins in venom of the deathstalker scorpion
Leiurus quinquestriaus (Buthidae): scyllatoxin (leiurotoxin I), a 31-residue
peptide; and agitoxin, a polypeptide with 38 amino acids, which can
severely affect pulmonary and cardiac systems leading to death of sting
victims. Images from RCSB PDB (www.rcsb.org): scyllatoxin, PDB ID
1SCY, Martins, J.C., Van de Ven, F.J., Rorremans, F.A., (1995) J. Mol.
Biol. 253: 590e603; agitoxin, PDB ID 1AGT, Krezel, A.M., Kasibhtla, C.,
Hidalgo, P., MacKinnon, R., Wagner, G. (1995) Protein Sci., 4:
1478e1489.
and loss of consciousness. In extreme cases, anaphylaxis
can be fatal, with approximately 60 people per year dying
in the United States (Schmidt, 2015). Despite this statistic,
the actual per capita incidence is low. Although approxi-
mately 7 million people in the United States are allergic to
insect stings, only one person per 100,000 allergic cases
dies each year.
ARTHROPOD VENOMS AS
ANTIMICROBIAL, ANALGESIC, AND
OTHER THERAPEUTIC AGENTS
Naturally occurring antimicrobial peptides (AMPs) pro-
duced by insects and arachnids have drawn increased in-
terest in recent years as alternatives to conventional
antibiotics. Their modes of action, effectiveness, and low
FIGURE 3.8 A potent polypeptide neurotoxin in venom of the Sydney
funnelweb spider, Atrax robustus (Hexathelidae); d-atracotoxin (robus-
toxin) can cause serious circulatory and respiratory failure in human bite
cases. Image from RCSB PDB (www.rcsb.org) PDB ID 1qdp; Pallaghy,
P.K., Alewood, D., Alewood, P.F., Norton, R.S. (1997) FEBS Lett. 419:
191e196.
resistance rates offer promising activity against bacteria,
fungi, viruses, and certain parasites. Melittin from honey
bees, for example, has been shown to inhibit bacteria,
including the Lyme disease agent Borrelia burgdorferi. It
also kills yeast (e.g., Candida albicans) and suppresses
Mycoplasma and Chlamydia infections. Solenopsin from
fire ants has been shown not only to be insecticidal but also
to exhibit antibacterial, antifungal, and antiviral activity.
Similarly, many antimicrobial peptides have been identified
in scorpions and spiders.
In addition to causing pain, peptides in the venoms of
many arthropods, particularly scorpions and spiders, can
act as analgesics, or painkillers. They typically affect
voltage-gated sodium channels of neurons, including
primary afferent nerve fibers associated with the pain
pathway. Interest has been focused on their potential as
therapeutic agents for modulating neural mechanisms
involved in chemical, mechanical, and thermal pain, in
addition to chronic pain. Venom of the Chinese
scorpion (Mesobuthus martensii) has been used since
ancient times in traditional Chinese medicine for the
treatment of pain. Among the insects, peptides in the
venom of several hymenopteran families are currently
under study as potential analgesics, including some wasps
(Sphecidae), tarantula hawks (Pompilidae), and velvet
ants (Mutillidae).
Venom peptides have also garnered significant
research interest in treating a number of human diseases
and other medical conditions. Melittin, from honey bees,
has been postulated to have potential for treating epilepsy

(A)
FIGURE 3.9 Tarantula hawk (Pompilidae, Pepsis chrysothemis), a wasp that can cause excruciating pain when it stings humans and other animals.
(A) Female feeding on milkweed flowers. (B) Sting on human finger; note the relatively unapparent reaction at the sting site, despite extreme pain.
(A) Photograph by Jillian Cowles; (B) Photograph by Justin O. Schmidt.
and acquired immune deficiency syndrome caused by the
Human immunodeficiency virus (HIV). Cantharidin, from
blister beetles, has long been used as an aphrodisiac, a
topical compound to remove warts, and a treatment for
other skin conditions such as molluscum contagiosum.
Pederin and its derivatives from staphylinid beetles have
been shown to inhibit protein and DNA synthesis and to
slow the division of cancer cells. Other antimicrobial
peptides in insect venoms have attracted attention as
possible alternative treatments of skin, eye, and lung
infections.
Scorpion venoms, in particular, are being studied
because of the therapeutic potential of specific peptides as
anticancer agents. A growing body of literature documents
the progress being made in medical research involving
breast, prostate, gastric, colorectal, lung, oral, and other
cancers. In addition, components of scorpion venoms are
drawing attention as possible future agents for treating cell-
mediated autoimmune diseases, including multiple
sclerosis.
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