Subtle Environmental Poisons and Disease – Part 1
The past series of posts have largely been preoccupied with the benefits to be had from ‘natural molecular space’, whether the molecules in question are large, small, or functionally linked together in complex (but useful) entire biosystems.
Obviously, some biomolecules are not merely useless, but may be actively harmful. There are a great many bioproducts which are of both high toxicity and obvious impact, at least to the unfortunate victims of serious or even life-threatening natural poisonings or envenomations. But toxic effects can be much more subtle, and therefore much less easily noticed. In fact, the insidious slowness of some toxic effects can render the actual molecular culprits very hard to pin down, and inevitably controversy is thus generated. These ‘subtle negative’ environmental influences are the principle theme for this discussion, which will include natural products, but will also heavily feature both artificial compounds and non-biological but ‘natural’ substances. (The quotation marks are used here since it is very often only through human activities that natural materials with potentially harmful effects are processed and brought into contact with sizable numbers of people).
What Does Subtlety Mean in a Toxic Context?
When we speak of a subtle toxic effect, what is actually meant? It might result from several factors, or any combination of them, including potency, exposure dose, frequency of exposure over time, and the in vivo persistence of the toxic substance. Any ingested toxic compound must by definition interfere with an important biochemical process, with ensuing negative consequences for the functioning of the organism. A poisonous substance might interact with many different biological molecules, but some of these will be of greater import than others in terms of how the resulting deleterious effects are produced. And the affinity of the poison for such biological targets is a determinant of potency.
Potency and dosage over time are inter-related. To qualify as ‘subtle’, intake of a highly potent compound (one whose toxic threshold is reached with very small amounts) would need to be in exceedingly low quantities, where no immediate effects are apparent. If that was the end to it, then obviously such a low-level exposure to the toxic agent has no further consequences. But a subtle deleterious effect might exist if the compound had produced some kind of persistent tissue or cellular damage, of a type that was very hard to detect without sophisticated intervention, and that was not at all appreciable by the individual concerned. Then, several possibilities could exist which in the end would result in a manifested disease state. Firstly, if the individual is re-exposed to the same source of the toxin on more than one occasion, the damage might be cumulative and accrete until it becomes of such significance that an overt illness is produced. If the body’s repair systems cannot comprehensively deal with the low-level induced damage, in some cases even long intervals between exposures might still result in noticeable pathology. But even if the repair is effective, regular intake of similar low doses of the toxic material over time might eventually overwhelm the host defenses, again leading to disease.
These scenarios assume repeated exposures, but even a single exposure could potentially have significant consequences. It might be supposed that a single bout of damage, if not fully repaired, might be another negative event in an individual’s ‘wear and tear’ list that increases with ageing. In other words, any such a low-grade but persistent toxic ‘insult’ might become more significant over time, in combination with other problems inevitably occurring through life. But a much more serious possibility also has been proposed, where short-lived exposure to certain chemical agents might actually set up an on-going pathological inflammatory process, even long after the original poison has been removed from the host system. This theme will be looked at in a little more detail in a later post in this series.
At this point, it’s very relevant to consider that there is an important issue relating to the physiological removal of toxic agents, or (in other words) how long it may be that noxious substances of any description can persist once taken into a host organism. Persistence has clear-cut implications for the ability of a substance to contribute to long-term and subtle deleterious effects. While water-soluble (hydrophilic) compounds are generally metabolized and excreted reasonably quickly, lipid-soluble (hydrophobic) compounds can be taken up by fat reserves and remain there for years, with only a slow diminution with time. A classic example in this regard is the insecticide DDT, whose tendency to persist in adipose (fat) tissue is well-described. Poisons which are themselves toxic elements obviously cannot be further ‘broken down’ chemically, and can persist through their interactions with normal biomolecules. For example, heavy metals such as lead and mercury can bind and inhibit numerous enzymes. Although the resulting complexes between metals and protein molecules may be physiologically degraded, release of the metal component may simply liberate it for another cycle of inhibition. In some cases, a noxious element may be physically or chemically similar to a normal biologically-used element, and replace it in certain biomolecules, with disastrous effects on metabolic activities. This is case for the toxic elements arsenic (capable of competing with phosphorus) and thallium (capable of competing with potassium).
Another major class of persistent and dangerous substances are certain mineral fibers, most notably asbestos. Poorly biodegraded long fibers (such as some mineral silicates, of which asbestos is a case in point) can persist indefinitely in specific anatomical sites. Although the mechanism is still incompletely understood, this can be associated with the generation of a chronic inflammatory process and ultimately carcinogenesis. The link between asbestos and mesothelioma is well recorded.
If we cast a wide enough net, another class of non-biological poisons must certainly be included: radionuclides, or radioactive isotopic versions of the elements. These can be either radioactive isotopic versions of normal elements of biological significance, or radioisotopes of non-biological elements. All such cases can be of either natural or artificial origins. Many examples of the former group can be cited, but potassium-40 (40K) is a natural radioisotope of interest, since it is contributes the largest portion of the radioactive background in living organisms. As such, it has been proposed as a major source of natural mutation, although experimental results have suggested that its contribution to mutation must indeed be (if anything) a subtle influence. Cases of relevant non-biological radioisotopes are likewise exceedingly numerous. Briefly, consider the example of polonium-210 (210Po), which can occur naturally, or can be generated by artificial nuclear reactions. This radioisotope is present in tobacco smoke, and it has been implicated as a major factor in the generation of smoking-induced cancer. Polonium-210 has also been in the news in recent years, through its use an exceedingly potent poison in the murder of the ex-Russian agent Alexander Litvinenko in London in 2006. There’s obviously nothing subtle about that, but as with any toxic agent, even polonium-210 can exert low-level effects if ingested in small enough doses. At that lower end of the exposure scale, the effects will vary among different individuals, but may contribute to cancers or other conditions, with an overall shortening of life expectancy.
Individual variation in responses to low-level toxic exposure reflect genetic variation in the metabolic processing of foreign compounds, or how the body reacts to the presence of noxious materials. There is much more to be said on this topic, which will be picked up at a later time within this series of posts. But for the time being, we can note this as one of a number of influences bearing on whether a low-level toxic exposure will have longer-term ‘subtle’ effects, depicted in the figure below:
A depiction of the range of various influences which can determine whether a substance could manifest a slow or insidious ‘subtle’ toxicity. Note that an implicit issue within ‘Generation of Ongoing Pathology’ is the ability of host systems to repair and contain toxic insults, as opposed to the generation of responses which are ultimately self-damaging.
The influence termed ‘cofactors’ in the above diagram simply refers to any other non-host factor which can interact with a proposed environmental toxic substance to exacerbate its action, or even be essential for the insidious toxic effect to be manifested in the first place. An interesting example is a putative requirement for the presence of simian virus 40 (SV40) for the generation of mesothelioma by asbestos.
For the rest of this post, I’ll move on to some specific examples of effects which have revealed subtlety in several senses of the word. The first case involves an artificial compound which is not strictly speaking an ‘environmental’ effect, since it required self-administration, if inadvertently. However, the experience with this compound has had many ramifications which do impinge on environmental influences, both man-made and natural.
(1) Parkinson’s Disease & Toxic Agents
In the early 1980s a remarkable series of events occurred which had implications across several fields of science and medicine. Although terrible and tragic in many ways, it provided a dramatic example of how a toxin can produce quite specific neurological effects, and had direct implications for the origins of Parkinson’s disease (PD). At that time in California, clinicians were confronted with a series of drug addicts in a state of ‘frozen’ mobility, which had many similarities to severe PD. Subsequent scientific detective work showed that this apparent similarity was more than just superficial. The sporadic condition of human PD is characterized by ongoing degeneration in a region of the brain called the substantia nigra, where destruction of neurons normally producing the crucial neurotransmitter dopamine leads to loss of muscular motor functions, eventually immobilizing the patient. These neurons are also pigmented, through the production of a type of melanin (‘neuromelanin’), an early observation which provided the name of this brain area (‘substantia nigra’ = Latin for ‘black substance’). A compound, L-dihydroxyphenylalanine (L-DOPA, which can access the brain and becomes metabolized to dopamine itself) can greatly alleviate symptoms, especially when first applied. The ‘frozen’ addicts likewise generally showed responsiveness to L-DOPA. By analyzing their common activities, the source of the problem was tracked down to their injection of a street drug preparation, a ‘synthetic heroin’, which in actuality was a botched attempt to make the drug meperidine (pethidine). The preparation that the clandestine chemists had produced contained sizable amounts of a different compound, N-methyl-4-phenyl-1,2,5,6-tetrahydopyridine (MPTP), eventually identified as the toxic culprit by means of animal testing. These studies also showed that MPTP ingestion resulted in specific damage to the substantia nigra, with associated loss of dopamine-producing neurons and the onset of parkinsonian symptoms.
Structures of some relevant molecules for the Parkinson’s / MPTP story. The amino acid phenylalanine is included as the precursor to dopamine, and to show its chemical similarity to L-DOPA. Meperidine is the drug towards which abortive synthetic attempts led to the formation of MPTP. MPP+ is the actively toxic metabolic product derived from MPTP itself.
The striking features of this story were widely reported in the scientific literature, and even found their way into popular fiction quite quickly. Those unmistakably victimized by MPTP had varying fates, ranging from death within a relatively short time, to survival for over a decade. But behind the initial cadre of severely affected patients, the prospect still remains of many more people developing PD from short-term exposure to MPTP (and initially subclinical damage) even decades ago. And this naturally raises one of the major implications of the whole MPTP saga: if a defined toxin can have such amazingly specific effects, could there not be other toxins in the environment with similar properties, which induce the neurodegeneration seen in ‘sporadic’ parkinsonian patients? In the course of these kinds of speculations, it was noted that the very description of this disease was a relative latecomer in 1817. Could the apparent lack of reporting of this disease in earlier times mean that ‘natural’ PD is actually a toxic condition, associated with the beginnings of the industrial revolution and newly introduced environmental pollutants?
Many studies have been conducted in order to evaluate this and related questions. In particular, exposure to certain insecticides has been a long-standing suspect as a potential agent of PD, but despite ‘probable cause’, this has not been firmly nailed down. These kinds of analyses must distinguish between genetic influences and environmental factors. (Many distinct genes are known to affect an individual’s susceptibility to PD, and this will be further considered in a subsequent post in this ‘subtle’ series). Studies with monozygotic (identical) twins illustrate this. In one detailed 1999 investigation, sets of monozygotic twins showed no significant differences in the concordance (common incidence in both twin pairs) of PD compared to non-identical twin pairs, but only (and this a crucial point) if the age of onset for either twin was after 51 years of age. Non-concordance of a disease in twin pairs in a controlled study is highly suggestive of environmental causes at least being contributing factors. Consider that if a disease does have a simple genetic origin, significant concordance would be expected in the (essentially) genetically identical pairs. Most cases of sporadic PD occur later in life, also consistent with (but far from proof of) a slow induction from environmental sources. But where PD does occur at younger ages, genetic influences (rare mutations, possibly in combination with environmental factors) might be postulated, and this is consistent with the higher concordance observed with identical twins with relatively young ages at the onset of PD. But the only general conclusion typically made at present is that the origin of sporadic PD is complex, with multiple genetic and environmental influences implicated directly or as suspects. And yet there is no question that, at least in certain genetic backgrounds, MPTP alone can induce a pathology with the key characteristics of PD. How does it do this?
A Stealth Poison At Work
Intensive studies on the mechanism of MPTP toxicity revealed that it was not the direct perpetrator of the neuronal damage. MPTP itself is acted upon by a specific enzyme within the brain, monoamine oxidase (MAO) B, which converts this compound into a positively charged species, the N-methyl-4-phenyl-pyridinium ion (MPP+, as shown in the above chemical structure figure). Consistent with this observation, inhibitors of MAO enzymes are protective against the effects of MPTP in animal models. MPP+ itself is capable of using the machinery for dopamine transport into neurons (using specific dopamine receptors), and this promotes its accumulation in very specific neuronal sites. It is important to note that this particular uptake mechanism also explains the high selectivity of MPTP (the precursor to MPP+) in its toxic action. Once taken up by dopamine neurons, MPP+ itself acts as a primary toxic agent towards mitochondria, through its inhibition of Complex I of the mitochondrial respiratory electron transport chain.
With the MPTP story, a series of processes are thus required for the ultimate toxic effect to be manifested: conversion to MPP+, uptake by dopamine neurons, and inhibition of mitochondrial activities. (These are primary factors; other issues such as specific genetic backgrounds certainly contribute to individual susceptibility, as will be discussed further in a subsequent post). So, it has been noted that this conjunction of requirements would (hopefully) render the occurrence of compounds with analogous properties to MPTP quite rare. With this in mind, are there natural precedents for this kind of noxious chemical agent? This raises the second case set to be considered (as noted above): natural toxic substances with ‘subtle’ actions. In many such circumstances, the subtlety is bound up with the difficulty of pinning down the true identity of the pathogenic culprit.
(2) Cycads, Soursops, and other ‘Environmental’ Neurological Diseases
In certain Western Pacific islands, epidemiologists have noted for decades an unusual incidence of a degenerative neurological condition called Amyotrophic Lateral Sclerosis / Parkinsonism-Dementia complex (ALS-PDC). In the language of the Chamorros of Guam, a people living on one of the afflicted island groups, the disease is known as ‘lytico-bodig’. A strong role for genetic influences in the origin of ALS-PDC seemed unlikely, given that it was recorded in diverse ethnic groups in varied Western Pacific locations. For a considerable time, though, a dietary item has been implicated: the consumption of a flour made from the seeds of cycad plants available in the affected locales. This remains unproven and controversial, particularly since a specific compound has not been conclusively identified. Yet the general ‘cycad hypothesis’ has support from a number of linked observations. Cycad flour fed to experimental animals over time induces a neurological condition with features of progressive parkinsonism, with associated damage to the substantia nigra. Also, the incidence of ALS-PDC has been in decline in recent years, and this correlates with changes in diet where the amounts of cycad-derived material have markedly declined. A specific amino acid, β-methylamino-L-alanine (BMAA; not found in normal proteins) has been repeatedly linked with cycad-induced disease, but proof of its role has consistently fallen short of the mark. Another contender is methylazoxymethanol (MAM, a metabolite derivative of the cycad compound cycasin), which has been shown to produce neurological genotoxicity.
Whatever the outcome of these studies, there is no question that raw cycad seeds (from which flour is derived) are quite poisonous, and this has long been known to Western Pacific peoples. But by using extensive washing and soaking procedures, they have ingeniously found a way to exploit this otherwise-useless material as a valuable foodstuff. The great irony implicit in the ‘cycad hypothesis’ is that although they succeeded in eliminating the acute toxicity of the cycad seeds, they could not remove traces of toxic substances which may have been the agents of subtle and insidious neurological damage.
Another potential natural molecular assailant of neurons is also found in an island setting, but in the West Indies. A high incidence of an ‘atypical’ parkinsonism has been identified on the island of Guadeloupe. (One example of the atypical nature of this condition is its failure to respond to L-DOPA.) This has been linked by epidemiological studies with the consumption of the tropical fruit called soursop, and a specific compound from this fruit (annonacin) has implicated as the probable underlying source of the pathology. Annonacin is an inhibitor of mitochondrial Complex I, and can also induce loss of dopamine neurons in the substantia nigra of experimental animals – findings which cannot help but stimulate recollection of the MPTP story, even if there are many points of divergence.
Finally, it’s interesting to note that both ALS-PDC of the Pacific and the Guadeloupe disease also have pathological features of ‘tauopathies’, or diseases associated with abnormal intercellular distribution of a protein called tau, which is normally found in conjunction with neuronal microtubules (a part of the cytoskeleton). In addition, one aspect of the neuropathy induced by annonacin is abnormal neuronal tau behavior. But a massively more frequent and consequential tauopathy is Alzheimer’s disease, so these findings raise the fascinating question as to whether environmental toxic agents might contribute to the burgeoning world-wide caseload of Alzheimer’s – and if so, how much, and under what genetic circumstances? The significance of such questions for public health in countries with increasingly ageing populations is obvious.
One point already alluded to above is the notion that a transient ‘hit and run’ exposure to a toxic substance might set up a continuous and actually self-perpetuating cycle of damage. Such a possibility could considerably complicate attempts to identify causative toxic agents. If a single short-live exposure (or transient set of exposures) to an agent can result in disease many years later, it is clear that fingering the original culprit becomes correspondingly more difficult. It remains a possibility that such effects are relevant to the cycad saga at least, but a more detailed consideration of this notion is a topic for a later post in this series.
In the meantime, a biopoly-verse rumination:
Bring genetics and host factors to view
Where some insidious poisons can brew
To stay and remain?
Or start off a chain
Of damage in an unfortunate few.
References & Details
(In order of citation, giving some key references where appropriate, but not an exhaustive coverage of the literature).
‘ A classic example in this regard is the insecticide DDT……’ (With respect to persistence in fat). See Turusov et al. 2002.
‘….arsenic (capable of replacing phosphorus) and thallium (capable of replacing potassium).’ With respect to arsenic, it is interesting to recall the recent controversy regarding ‘arsenical life’, where arsenic in a specific bacterium was reputedly replacing phosphorus (see a previous post for brief detail on this). Arsenic can compete with phosphorus when it is in the form of arsenate (See Kaur et al. 2011; and also Dani 2011 for a discussion of the biological significance of this). For more details regarding thallium and its competition with potassium, see Hoffman 2003.
‘….release of the metal component may simply liberate it for another cycle of inhibition. This can be overcome if a chemical agent (a chelator) is administered which is capable of tightly binding the metal, solubilizing it, and allowing it to be excreted. See Flora & Pachauri 2010; Jang & Hoffman 2011.
‘….potassium-40 (40K) …. has been proposed as a major source of natural mutation, although experimental results suggest that its contribution to mutation must indeed be subtle influence.’ See Gevertz et al. 1985 for more detail and a refutation of the importance of this radioisotope for mutation, at least in bacteria.
‘…..polonium-210 (210Po), …is present in tobacco smoke, and it has been attributed a major role in the generation of smoking-induced cancer….’ See Zagà et al. 2010.
‘ Polonium-210 has been in the news in recent years, through its use an exceedingly potent poison in the murder of the Russian Alexander Litvinenko…..’ Polonium-210 is an α-emitter (Helium-4 nuclei). While these emitted particles are relatively massive and poorly penetrating, they are very dangerous if an α-source has been ingested. Doses as little as 1 μg may be lethal in susceptible individuals, and doses of several hundred μg will be universally fatal. See Scott 2007. For more details on the Litvinenko case, see a BBC timeline article.
‘….polonium-210 can exert low-level effects if ingested in small enough doses.’ See also Scott 2007.
‘ The influence termed ‘cofactors’ ….. example is a putative requirement for the presence of simian virus 40 (SV40) for the generation of mesothelioma by asbestos….’ See Rivera et al. 2008; Qi et al. 2011. Note that SV40 was a contaminant of early Salk polio vaccine preparations (see Vilchez & Butel 2004).
‘….origins of Parkinson’s disease…..’ This disease (the ‘shaking palsy’) was first described in the early 19th century by Dr. James Parkinson (Thomas & Beale 2007), who thus bequeathed his name to it. Although obviously an eponymous title, the “Parkinson” is often now rendered with a lower-case ‘P’.
‘ These neurons are also pigmented…..’ Melanocytes, the cells in the skin which produce the pigment melanin responsible for skin color (along with the related pigment pheomelanin) are derived from the same embryological origins as neurons, the neural crest.
‘….a type of melanin (‘neuromelanin’)….’ Neuromelanin is chemically similar, but not identical to, the black melanocyte pigment, which itself is often termed ‘eumelanin’. See Zecca et al. 2001.
‘…..the source of the problem [Parkinson-like illness] was tracked down…..’ See Langston et al. 1983.
‘….widely reported in the scientific literature….’ For example, see an article in 1984 by Roger Lewin in Science, whose title (‘Trail of Ironies to Parkinson’s Disease’) speaks for itself.
‘…even found their way into popular fiction quite quickly….’ The well-known ‘new wave’ science fiction novel Neuromancer by William Gibson (Ace Science Fiction, 1984) features a particular scene where an individual is deliberately victimized by means of the nasty aspects of MPTP neurotoxicity. Since the book was first published in 1984, this was at the time a very quick uptake on a scientific and medical development.
‘ Those unmistakably victimized by MPTP had varying fates…..’ See Langston’s popular book (co-authored with Jon Palfreman), The Case of the Frozen Addicts (Pantheon, 1995). Also see a Wired magazine article.
‘…..a relative latecomer in 1817…..’ See the above note about James Parkinson.
‘….‘natural’ PD …. a toxic condition…?’ See Calne & Langston 1983.
‘….exposure to insecticides ….as a potential agent of PD …. not been firmly nailed down…’ See Brown et al. 2006.
‘ Most cases of sporadic PD occur later in life….’ Only 1-3% of total PD cases can be attributable to direct genetic causes (See Lorinicz 2006).
‘….MPTP itself is acted upon by a specific enzyme with the brain, monoamine oxidase….’ See Herraiz 2011 (a).
‘…..inhibitors of MAO enzymes are protective against the effects of MPTP…..’ Herraiz 2011 (b).
‘….also explains the high selectivity of MPTP (the precursor to MPP+) in its toxic action…’ For an early report on MPP+ uptake, see Javitch et al. 1985.
‘….it [MPP+] acts as a primary toxic agent towards mitochondria….’ For a little more detail on mitochondrial activity, see a previous post. For more on Complex I in general, and with respect to MPTP / MPP+, see Schapira 2010.
‘….epidemiologists have noted an unusual incidence ….ALS-PDC…’ For an entertaining account of the history of this topic, see The Island of the Colour-blind (Picador, 1996; Book Two, Cycad Island) by the famous neurologist Oliver Sacks. For a general overview of ALS-PD, see Steele 2005.
‘ Cycad flour fed to experimental animals…..’ See Shen et al. 2010.
‘ A specific amino acid …BMAA….has been repeatedly linked with cycad-induced disease…’ For a review and disputation of this, see Snyder & Marler 2011.
‘ Another contender is methylazoxymethanol….’ See Kisby et al. 2011.
‘….a specific compound from this fruit (annonacin) has implicated….’ See Champy et al. 2004; Lannuzel et al. 2008. Other compounds chemically related to annonacin have also been implicated: See Alvarez Colom et al. 2009.
‘…one aspect of the neuropathy induced by annonacin is abnormal neuronal tau behavior…’ See Escobar-Khondiker et al. 2007.
Next Post: This is the last post for 2011; will be back early next year.