Consumption of unregulated food items (false morels) and risk for neurodegenerative disease… UDC 613.2:616.8-00 Read DOI: 10.21668/health.risk/2020.3.11.eng online Research article CONSUMPTION OF UNREGULATED FOOD ITEMS (FALSE MORELS) AND RISK FOR NEURODEGENERATIVE DISEASE (AMYOTROPHIC LATERAL SCLEROSIS) P.S. Spencer Oregon Health & Science University, Portland, Oregon, 97201, USA Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of high- incidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/post- mitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are under- way in Western Europe and USA to determine if the practice is associated with sporadic ALS. Key words: Amyotrophic lateral sclerosis, cycad seed, cycasin, gyromitrin, DNA damage, Guam, Finland, Russia, USA. While a small percentage of human neu- the neurotoxic seed of cycad gymnosperms rodegenerative diseases has a genetic origin, (Cycas spp.) for food (Guam) and/or medi- the large majority occurs sporadically. Disor- cine (Guam, Kii, Papua). These traditional ders such as amyotrophic lateral sclerosis practices have been associated with ALS in (ALS) are believed to result from the action all three pockets of neurodegenerative dis- of unknown environmental factors on indi- ease, although the strongest epidemiological viduals with an underlying genetic suscepti- evidence comes from Guam [2]. bility [1]. Evidence for the primary or exclu- Cycad Toxins. Cycad seed linked to sive role of an environmental trigger comes Western Pacific ALS contain cycasin (2–4 % from longitudinal observation of Western Pa- w/w) and smaller amounts of the nonprotein cific ALS [2]. This neurodegenerative disor- amino acid β-N-methylamino-L-alanine der was formerly present in very high inci- (L-BMAA), both of which have genotoxic dence among populations in the Mariana Is- and neurotoxic potential. The concentration land of Guam (USA), the Kii Peninsula of of cycasin (but not of L-BMAA) in flour de- Honshu Island (Japan), and Papua Province, rived from washed cycad seed used by Gua- west New Guinea (Indonesia). However, over manians for food was strongly associated the past seven decades, the incidence of ALS with ALS among males and females [4]. Cy- has declined in all three populations, with casin (methylazoxymethanol-β-D-glucoside) disappearance of the disease on Guam [3]. is metabolized by plant, animal and human This has coincided with population develop- glucosidases to form methylazoxymethanol ment and acculturation to modernity during (MAM), which in turns forms methyl free which traditional practices progressively de- radicals that damage cellular DNA [5]. clined. Discontinued practices include use of MAM-induced DNA damage in cycling cells __________________________ Spencer P.S., 2020 Peter S. Spenser – Professor (e-mail: [email protected]; tel.: +1 503-494-1085; ORCID: https://orcid.org/0000-0003-3994-2639). ISSN (Print) 2308-1155 ISSN (Online) 2308-1163 ISSN (Eng-online) 2542-2308 93 P.S. Spencer may trigger mutations that lead to uncon- might trigger long-latency neurodegenera- trolled mitosis and tumorigenesis, a property tion culminating in ALS or a related brain used experimentally to generate an animal disease [11]. model of colon cancer. MAM is also a potent Food Use of Certain Ascomycetes Fungi. developmental neurotoxin that disrupts the Distribution. The False Morel G. escu- development of rodent brain and activates lenta has a very wide distribution, including cellular pathways associated with both cancer the entire continent of Europe, especially and neurodegeneration [6]. Germany and Poland. It is also found False Morel Toxins. Methyl (carbon- throughout Asia, everywhere from Russia to centered) free radicals are also generated by Indonesia. In North America, it occurs from hydrazine compounds that are mechanisti- Mexico to Alaska, especially in the U.S. cally related to MAM [7]. Hydrazine is used Midwest, Pacific Northwest, and the Rock- in agricultural chemicals (pesticides), chemi- ies. G. esculenta also occurs in North Africa cal blowing agents, pharmaceutical interme- and the Middle East regions around the diates, photography chemicals, boiler water Mediterranean Sea. treatment for corrosion protection, textile Europe and USA. Consumption of wild dyes, and as fuel for rockets, spacecraft and mushrooms, which include False Morels emergency power units in certain military jet (Gyromitre, fausse morille, morille brune) aircraft [8]. For present purposes, however, and True Morels (Morchella spp.), has been the most relevant potential exposure to hy- identified as a risk factor for a cluster of drazine compounds is from the consumption 12 ALS patients in a small community in of certain fungal species. The commercially Savoie in the French Alps [11]. While True available and widely eaten Button Mush- Morels (morille) are highly prized as a deli- room (Agaricus bisporus Lange) contains up cacy in Europe and beyond, it can be diffi- to 0.04 % agaritine (β-N-[γ-L-(+)-glutamyl]- cult to distinguish them anatomically from 4-hydroxymethylphenylhydrazine) and 4-hyd- poisonous False Morels. Consumption of roxymethylphenylhydrazine) [9]. Of interest False Morels is also documented elsewhere here, however, are the highly poisonous in Europe (Finland) and the USA, especially False Morel mushrooms (Gyromitra, in the State of Michigan, where the local Helvella and Verpa spp.), notably Gyromitra Poison Control Center historically has re- esculenta Pers. (Figure); this species con- ceived the highest number of MMH mush- tains 0.3 % gyromitrin (acetaldehyde-N- room-related calls [13, 14]. Eight to ten spe- methyl-N-formylhydrazone), the hydrolysis cies of Gyromitra exist on the North American of which forms DNA-damaging methylating continent, including G. montana Harmaja agents, namely N-methyl-N-formylhydrazine (possibly G. gigas), which reportedly has been (MFH) and N-monomethylhydrazine (MMH), collected from the West Coast of the USA and by further hydrolysis of MFH [10]. The risk sold through intermediaries for use in restau- of long-term adverse health effects from rants in the State of Florida [15, 16]. consumption of Gyromitra esculenta may be Finland. False Morels are considered a greater in individuals with genetic slow ace- delicacy in Finland [10]. The Finnish Food tylation rates, which would result in larger Authority recommends extensive washing amounts of MMH formed from gyromitrin and double boiling prior to their ingestion and [10]. Since hydrazines and MAM induce the advises against ingestion by children and same type of DNA damage, it is hypothe- pregnant and breastfeeding women because of sized that single or repeated exposure to «residues of the toxin gyromitrin despite methyl free-radical-generating hydrazines processing» [17]. However, in previous dec- 94 Health Risk Analysis. 2020. no. 3 Consumption of unregulated food items (false morels) and risk for neurodegenerative disease… ades, dried, or once-boiled fresh False Morels tion of G. esculenta (May) or, in August- were considered safe to eat. During and after September, G. gigas Krombh (Snow or Rus- the Finnish Winter War with Russia (Novem- sian Autumn Morel) [21, 22]. Another False ber 30, 1939 – March 12, 1940), there was a Morel, Verpa bohemica Krombh, is said to be mass migration of Karelians to Finland and sold frozen in Russia and eaten by many Rus- particularly to the southeast (Itä-Suomi) sian people [23, 24]. Consumption of large where there is a strong mushroom-eating cul- amounts of V. bohemica in a single sitting, or ture, including MMH-generating G. esculenta on successive days, has been reported to cause (Korvasieni) among Karelians. Between 1914 a gyromitrin-like syndrome in susceptible in- and 1945, one quarter of the number of acute dividuals [25]. G. korshinskii Jacz. (Round poisonings attributed to G. esculenta occurred Spored False Morel) has been described across in southeastern Finland [18]. Consumption of the entire Russian Federation [26]. Gyromitra spp. can trigger acute gastrointes- tinal (nausea, vomiting, diarrhea) and neuro- toxic effects (headache, vertigo, ataxia, fever, muscle fasciculation, seizures, coma, death) [19]. Notably, the birth location of a cluster of ALS subjects in Finland corresponds to a region of False Morel consumption [20]. The cluster involved a population of half a million subjects residing in parts of the Finnish prov- inces of Kuopio, Mikkeli, and Pohjois- Karjala, as well as parts of present-day Rus- sian Karelia. ALS rates were 225 % higher among Finnish WWII evacuees from Karelia (18 per 100,000) compared with non- Figure. False morel mushroom (Gyromitra esculenta, Strochok) near Lenin Trail in area of Razliv near evacuees (8 per 100,000). As noted by the Dibuny, north-west from Saint Petersburg, Russia. authors, these data speak against a genetic Leninskaya Tropa, Pesochny, Sankt-Peterburg, Russia etiology for ALS and for exposure to one or more environmental factors that made the There are no data to suggest any long-