Submitted to: Food and Chemical Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2012
Publication Date: 6/1/2012
Citation: Green, B.T., Lee, S.T., Panter, K.E., Brown, D.R. 2012. Piperidine alkaloids: Human and food animal teratogens. Food and Chemical Toxicology. 50(6): 2049-55.
Interpretive Summary: 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 carry teratogenic risks in humans due to potential exposure from tobacco consumption and/or tobacco replacement therapy (Slotkin, 2008). Tobacco use by pregnant women is associated with many types of birth defects including cleft palates and lips ( [Shaw et al., 2009] and [Hackshaw et al., 2011]). A recent meta-analysis by Hackshaw et al. (2011) calculated an odds ratio of 1.28 indicating a 28% increased incidence of cleft lip or palate in children from mothers that used tobacco during pregnancy. Moreover, an epidemiological survey of eleven states in the US estimated the prevalence of these defects at 6.39–10.48 per 10,000 live births (NIDCR, 2011). This represents approximately 6000–7000 live births with palate or lip defects annually in the United States (CDC, 2006), with a reported lifetime medical burden of $697 million for treating children born each year with oral clefts (NIDCR, 2011). A greater understanding of the mechanism(s) behind oral cleft formation in humans will have significant impact in reducing their incidence, decreasing overall medical costs and the emotional impacts to families and individuals. For example, nicotine replacement therapy is currently being investigated for use by pregnant smokers, although, it is not without controversy ( [Forest, 2010] and [Coleman et al., 2011]). For women who are unable to quit using tobacco during pregnancy, nicotine (7) replacement therapy may provide a means to prevent the exposure of teratogenic piperidine alkaloids to the developing fetus and thereby reduce the risk of MCC defects and oral clefts in their children. The premise of this recommendation is based on in vitro results from cell-based studies of human fetal muscle-type nAChR expressed by TE-671 cells, in vivo results from the exposure of pregnant livestock to piperidine alkaloid teratogens, and human epidemiological data which have documented an association between tobacco use by pregnant women and oral clefts in their children. Continued and expanded research on the molecular mechanisms behind the teratogenic effects of piperidine alkaloids is needed, and will provide benefits for both humans and livestock through decreased associated medical costs, improved livestock production systems, and associated economic gains to agricultural producers.
Technical Abstract: Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure–activity relationships and their potential implications for human health.