ReviewPiperidine alkaloids: Human and food animal teratogens
Highlights
► Piperidine alkaloid intoxication has significant public health consequences. ► Piperidine alkaloids are acutely toxic and teratogenic to the developing fetus. ► Maternal tobacco use in humans is associated with increased MCC in their children.
Introduction
Piperidine alkaloids, which possess a characteristic saturated heterocyclic ring structure, occupy a special place in the annals of human and livestock poisoning (Fig. 1). Perhaps the first notable example of poisoning by a member of this alkaloid group was the death of Socrates in 399 B.C. According to the famous account by Plato in Phaedo, the philosopher ingested poison hemlock (Conium maculatum), a plant containing high concentrations of coniine (2) and γ-coniceine (1) (Reynolds, 2005). In the popular literature, Agatha Christie continued this theme in a story plot involving a poison hemlock extract said to be high in coniine (2) as a means to commit murder in her book Murder in Retrospect (1984). Nicotine (7) in domestic tobacco (Nicotiana tabacum) as well as the pure alkaloid has been implicated in numerous cases of mild to severe acute toxicoses in humans (Gehlbach et al., 1974, Hagiya et al., 2010, Schep et al., 2009). Similarly, ingestion of lupines (Lupinus spp.) in the form of bitter lupine flour (principal toxicant: lupinine) and Laburnum spp. pods (principal toxicant: cytisine) have produced acute poisoning in humans (Pingault et al., 2009, Schep et al., 2009). Consumption of poisonous plants with high concentrations of piperidine alkaloids can produce acute intoxications in adult animals as well (Panter et al., 1999). Clinical signs of acute piperidine alkaloid toxicity in livestock include frequent urination, defecation, tachycardia, muscle weakness, muscle fasciculations, ataxia, collapse and ultimately death due to respiratory failure (Panter et al., 1988a,b).
The acute toxicoses produced by plant piperidine alkaloids have been attributed to their ability to desensitize nicotinic acetylcholine receptors (nAChRs) (Green et al., 2010). These receptor targets are ligand-gated cation channels, which mediate the actions of acetylcholine in excitatory neurotransmission within the peripheral and central nervous systems (Buccafusco, 2004). There are in excess of twenty subtypes of multi-subunit nAChRs, which are expressed in neurons and several non-neuronal cell types, including lymphocytes, skin cells and airway epithelia (Wessler and Kirkpatrick, 2008). Nicotine (7) and related alkaloids initially stimulate these receptors, but their persistence at their sites of action lead to receptor desensitization and inhibition of cation (Na+, Ca2+ and K+) conductances. Through their actions at nAChRs in the neuromuscular junction for example, nicotinoid alkaloids evoke transient skeletal muscle fasciculations that are rapidly followed by paralysis, progressing to respiratory failure. In adult animals, these muscle-type nAChRs consist of five associated subunits: two alpha, one beta, delta, and epsilon subunit that form a cation conductance channel. The two alpha-subunits are the main binding sites for acetylcholine and the adjacent delta and epsilon subunits play a complementary role in the receptor–ligand interaction (Arias, 2000). Fetal muscle-type nAChRs have a similar pentameric composition, except that they possess a gamma subunit in place of the epsilon subunit as the latter is expressed postnatally (Mishina et al., 1986).
As dramatic as acute toxicoses may be, sub-acute intoxication of pregnant livestock by piperidine alkaloids is a more common occurrence and has significant economic consequences to livestock producers (Keeler et al., 1993). Alkaloids ingested by the pregnant female can accumulate in the relatively more acidic blood of the conceptus (Neubert, 1988). Piperidine alkaloids, found in many poisonous plants including domestic tobacco, poison hemlock, wild tree tobacco (Nicotiana glauca), and lupine, can produce fetal deformities such as multiple congenital contractures (MCC) and cleft palates (CP) in the offspring of grazing livestock (Panter et al., 1990). MCC defects typically consist of arthrogryposis, scoliosis, torticollis, kyposis, and lordosis (Panter and Keeler, 1992, Panter and Keeler, 1993). In utero exposure to piperidine alkaloids is not limited to livestock. Maternal tobacco use exposes the developing human fetus to nicotine (7), which has a myriad of adverse effects on fetal development and is considered to be a neuro-teratogen (for review see Bruin et al., 2010, Dwyer et al., 2009). These adverse development effects include congenital arthrogryposis (O’Flaherty, 2001, Polizzi et al., 2000, Shi et al., 2008, Steinlein, 2007). All forms of arthrogryposis in humans and livestock manifest multiple joint contractures, attributable to decreased fetal movements during development (Fig. 2; Panter et al., 1990, Weinzweig et al., 2008). These multiple joint contractures were also produced in animal models by the administration of neuromuscular blocking agents such as d-tubocurarine, or specific piperidine alkaloids like anabasine (4) (Moessinger, 1983, Panter et al., 1999).
Cleft palates in cattle and goats can also result from the lack of fetal movements in the head and neck regions, resulting in the tongue preventing normal palate closure during early fetal or late embryo development. The resulting mechanical interference of the tongue between the palate shelves at the time of closure results in the formation of a cleft (Fig. 3; Panter and Keeler, 1992, Panter et al., 1998a). The period of gestation when a fetus is susceptible to these plant teratogens varies according to the livestock species, the specific piperidine alkaloid, and the length of time exposed; but, in general, susceptible periods are 30–50 days for CP and 50–100 days for contracture defects of the forelimbs, spine and neck, and there must be continuous inhibition of fetal movement for defects to occur (Panter et al., 1992). Anabasine (4), a piperidine alkaloid that is associated with CP in goats (Panter et al., 1999), may similarly affect the developing human fetus in utero secondary to maternal tobacco use.
Section snippets
Structure–teratogenicity relationships of piperidine alkaloids
The initial work on structure–teratogenicity relationships of piperidine alkaloids from poisonous plants was performed by Keeler and Balls (Keeler and Balls, 1978). Using poison hemlock as a starting point, the researchers determined that coniine (2) (2-propylpiperidine) and γ-coniceine (1) (2n-propyl-Δ1-piperidine) could produce MCC defects in the offspring of pregnant cows dosed with plant that had high concentrations of either piperidine alkaloid. Both of these teratogens have a three-carbon
Ammodendrine (6) and N-acetylhystrine (5)
Ammodendrine (6) is a teratogenic piperidine alkaloid found in lupine species as a mixture of enantiomers; it is a partial agonist at nAChRs with an EC50 for the racemate that exceeds 500 μM in TE-671 cells (Table 1; Green et al., 2010, Daly, 2005, Lee et al., 2008a, Panter et al., 1994, Keeler and Panter, 1989). The 50% lethal dose (LD50) of ammodendrine (6) in a mouse-based bioassay ranges from 94 to 134 mg/kg depending on the form of the alkaloid (Table 1; Lee et al., 2005). N-Acetylhystrine (5
Summary and implications for human health
Piperidine alkaloids from poisonous plants have provided insights into the mechanisms underlying MCC defects and CP in livestock and humans. They accumulate in fetal blood and act at fetal nAChRs, which may be more susceptible to them than adult receptors. Their teratogenic actions are hypothesized to involve persistent nAChR desensitization; leading to an inhibition of fetal movements. Through this proposed mechanism, livestock teratogens such as anabasine (4) and anabaseine (3) could also
Conflict of Interest
There are no conflicts of interest associated with this work.
Acknowledgements
The authors thank Terrie Wierenga for expert assistance with the figures and Isabelle McCollum and Amber Whittaker for assistance with the manuscript. This work was supported by USDA/ARS. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture.
References (103)
Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors
Neurochem. Int.
(2000)- et al.
A chlorinated amide and piperidine alkaloids from Aloe sabaea
Phytochemistry
(2000) Tobacco: a cause of congenital arthrogryposis
- et al.
Minor alkaloids of tobacco release [3H]dopamine from superfused rat striatal slices
Eur. J. Pharmacol.
(1995) - et al.
The dynamic effects of nicotine on the developing brain
Pharmacol. Ther.
(2009) - et al.
Desensitization of nicotinic ACh receptors: shaping cholinergic signaling
Trends Neurosci.
(2005) - et al.
Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors
Neurotoxicol. Teratol.
(2010) - et al.
Analyses of tobacco alkaloids by cation-selective exhaustive injection sweeping microemulsion electrokinetic chromatography
J. Chromatogr. A
(2007) - et al.
A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus
Neurosci. Lett.
(1994) A study of the occurrence of anabaseine in Paranemertes and other nemertines
Toxicon
(1971)
Relative toxicities and neuromuscular nicotinic receptor agonistic potencies of anabasine enantiomers and anabaseine
Neurotoxicol. Teratol.
The up-and-down method substantially reduces the number of animals required to determine antinociceptive ED50 values
J. Pharmacol. Toxicol. Methods
Enantiomeric analysis of anatabine, nornicotine and anabasine in commercial tobacco by multi-dimensional gas chromatography and mass spectrometry
J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci.
Biochemistry of hemlock (Conium maculatum L.) alkaloids and their acute and chronic toxicity in livestock
A Rev. Toxicon.
Neuromuscular blockade after ingestion of tree tobacco (Nicotiana glauca)
Ann. Emerg. Med.
A tobacco related epidemic of congenital limb deformities in swine
Environ. Res.
A novel validated procedure for the determination of nicotine, eight nicotine metabolites and two minor tobacco alkaloids in human plasma or urine by solid-phase extraction coupled with liquid chromatography-electrospray ionization–tandem mass spectrometry
J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci.
Quinolizidine and piperidine alkaloid teratogens from poisonous plants and their mechanism of action in animals
Vt. Clin. N. Am-Food A.
Crooked calf syndrome: managing lupines on rangelands of the channel scablands of East-Central Washington State
Rangelands
Hemlock alkaloids from Socrates to poison aloes
Phytochemistry
Mid-pregnancy cotinine and risks of orofacial clefts and neural tube defects
J. Pediatr.
If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents?
Neurotoxicol. Teratol.
Accidental fatal poisoning by Nicotiana glauca: identification of anabasine by high performance liquid chromatography/photodiode array/mass spectrometry
Forensic Sci. Int.
Genetic disorders caused by mutated acetylcholine receptors
Life Sci.
Poison hemlock (Conium maculatum L.)
Food Chem. Toxicol.
Desensitized nicotinic receptors in brain
Brain Res. Brain Res. Rev.
Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors
Br. J. Pharmacol.
Dufour’s gland and poison gland chemistry of the myrmicine and, Messor capensis (Mayr)
J. Chem. Ecol.
Long-term consequences of fetal and neonatal nicotine exposure: a critical review
Toxicol. Sci.
Chemical profile of two types of oral snuff tobacco
Food Chem. Toxicol.
Neuronal nicotinic receptor subtypes: defining therapeutic targets
Mol. Interv.
A fatal poisoning from Nicotiana glauca
J. Toxicol. Clin. Toxicol.
Improved national prevalence estimates for 18 selected major birth defects – United States, 1999–2001
MMWR Morb. Mortal. Wkly. Rep.
Murder in Retrospect
The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats
Int. J. Neuropsychopharmacol.
Efficacy and safety of nicotine replacement therapy for smoking cessation in pregnancy: systematic review and meta-analysis
Addiction
Skeletal anomalies in pigs associated with tobacco
Mod. Vet. Pract.
Congenital arthrogryposis associated with ingestion of tobacco stalks by pregnant sows
J. Am. Vet. Med. Assoc.
Congenital arthrogryposis in offspring of sows fed tobacco (Nicotiana tabacum)
Am. J. Vet. Res.
Nicotinic agonists, antagonists, and modulators from natural sources
Cell. Mol. Neurobiol.
The A622 gene in Nicotiana glauca: evidence for a functional role in pyridine alkaloid synthesis
Plant Mol. Biol.
Nicotine content and delivery across tobacco products
Handb. Exp. Pharmacol.
Hemlock alkaloids in aloes. occurrence and distribution of gamma-coniceine
Planta Med.
Mass spectrometry in structural and stereochemical problems. LXXII. A study of the fragmentation processes of some tobacco alkaloids
J. Am. Chem. Soc.
Poisoning and congenital malformations associated with consumption of poison hemlock by sows
J. Am. Vet. Med. Assoc.
Alkaloid studies. LXVII.1 Novel piperidyl alkaloids from Lupinus formosus
J. Org. Chem.
Controversy and evidence about nicotine replacement therapy in pregnancy
MCN. Am. J. Matern. Child. Nurs.
Evaluation of developmental toxicity of coniine to rats and rabbits
Teratology
Effect of coniine on the developing chick embryo
Teratology
Nicotiana glauca (tree tobacco) intoxication–two cases in one family
J. Med. Toxicol.
Cited by (50)
Toxic plants
2022, Reproductive and Developmental ToxicologyTeratogenic effects of Bocconia frutescens L.
2020, Journal of Developmental Origins of Health and DiseaseUnderstanding the Chemical Exposome During Fetal Development and Early Childhood: A Review
2023, Annual Review of Pharmacology and Toxicology