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Ciguatoxin
Ciguatoxin MA Darracq, University of California, San Diego, CA, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by David Eldridge and Christopher P. Holstege, volume 1, pp 610–611, Ó 2005, Elsevier Inc.
Chemical Profile l
Synonyms: CTX 1, P-CTX 1, Pacific ciguatoxin 1 Molecular Formula: C60H86O19 l Chemical Structure: l
Background The ciguatoxins are a group of heat-stable, colorless, odorless, and lipid-soluble compounds with a polyether ring structure. They bind avidly to and open voltage-gated sodium channels with symptoms of characteristic neuroexcitability that may last for days to months. There are 12 known ciguatoxins found in Caribbean and tropical Atlantic waters and 29 reported ciguatoxins in Pacific waters. Ciguatoxins may be found in the flesh and viscera of predatory coral-reef fish from waters predominantly between 35 south and 35 north latitude. Implicated species of fish are predatory reef fish, including Amberjack, Barracuda, Cinnamon, Coral trout, Dolphin, Eel, Emperor, Spanish mackerel, Surgeon fish, Grouper, Kingfish, Paddletail,
Encyclopedia of Toxicology, Volume 1
Parrot fish, Red snapper, Reef cord, Sea bass, Swordfish, and Yankee whiting. Ciguatera poisoning may occur after consumption of these fish. Ciguatera poisoning is also known as ciguatera fish poisoning or ichthyosarcotoxism. Unfortunately, ciguatoxin-
containing fish look, smell, and taste normal, thereby preventing easy identification of contaminated fish. Laboratorybased detection methods (gas and liquid chromatography/ mass spectroscopy) for the presence of ciguatoxins in fish are available; however, they remain labor and time intensive. To date, there are no laboratory tests commercially available for the detection of ciguatoxins in human blood and diagnosis remains based on the characteristic signs and symptoms and on the history of fish consumption. Expanding trade from ciguatoxin endemic areas has contributed to a wider distribution and increasing frequency of reported disease in nonendemic areas where poisoning may be underrecognized or under appreciated. Ciguatera is responsible for the highest reported incidence of food-borne illness attributable to finfish in the United States
http://dx.doi.org/10.1016/B978-0-12-386454-3.00712-0
963
964
Ciguatoxin
and worldwide with 50 000 cases reported annually; however, underreporting is likely in endemic areas. Most exposures are reported following the exposure to fish caught in Pacific, Indian, or Caribbean waters.
Exposure Routes and Pathways Ciguatera occurs after the consumption of ciguatoxic fish listed above, including Grouper, Red snapper, Barracuda, and Amberjack. These large carnivorous and predatory reef fish accumulate toxin after consumption of smaller reef fish, which have fed on toxic dinoflagellates such as Gambierdiscus toxicus and related species. Bottom-dwelling dinoflagellates synthesize ciguatoxins for unclear purposes. Ciguatoxins become concentrated up the food chain, with humans at the top. Contaminated fish accumulate ciguatoxins in the flesh, muscle, skin, and viscera. In Pacific waters, as ciguatoxin moves up the food chain, biotransformation occurs resulting in a more oxidized form of ciguatoxin with increased toxicity. Ciguatoxin is one of the most potent natural toxins known. One pacific ciguatoxin (P-CTX-1) poses a health risk at concentrations as low as 0.08–0.1 mg kg 1 in man. Most fish do not concentrate sufficient ciguatoxin to be lethal to humans. Neither cooking nor freezing can inactivate the toxin. Fishermen in endemic areas may rub fish organ tissue across their gums to determine safety with the sensation of tingling denoting an unsafe fish.
Toxicokinetics Signs and symptoms of toxicity occur 30 min to 30 h (average 6 h) after consumption of the contaminated fish. To date, no study has evaluated the toxicokinetics of ciguatoxin in humans. A rat model using one of the Pacific ciguatoxins (P-CTX-1) demonstrated a peak blood concentration at 1.97 h after oral exposure. Ciguatoxin elimination from the blood was slow with a terminal half-life of 82 h. Ciguatoxin activity was measured in rat liver, muscle, and brain 96 h after exposure. Small amounts of ciguatoxin appeared in the urine; however, the main route of excretion was in the feces.
Mechanism of Toxicity Ciguatoxins have been demonstrated to bind to and modulate the activity of cell membrane voltage-gated sodium channels. Ciguatoxins bind at site 5 on the alpha subunit, resulting in the opening of the channels at resting membrane potential. Sodium influx causes membrane depolarization and spontaneous or repetitive firing of action potentials. In vitro studies using mammalian dorsal root ganglia demonstrated an increased recovery of sodium channels from the inactivated state with resultant neuroexcitability. The influx of sodium into the neuronal tissue results in cellular swelling with decreased conduction velocity and neurotransmission. This excess neuroexcitation is thought to be the etiology of the neurological symptoms often described by patients. Recovery from ciguatoxin binding and modulation may take months to years as new receptors are synthesized.
Acute and Short-Term Toxicity (or Exposure) Human Gastrointestinal and neurological symptoms are most commonly described following ciguatoxin exposure; however, the pattern is highly geographically variable and likely reflects differences in the effects and relative potencies of different types of ciguatoxins. In the Caribbean, gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain are reported to occur prior to the development of neurological symptoms. In Pacific and Indian waters, neurological symptoms predominate with minimal gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain may occur within 6–24 h of consumption of fish with spontaneous resolution in 1–4 days. Early in the disease course, cardiovascular toxicity manifested by hypotension and bradycardia may occur and requires prompt resuscitative medical care. Neurological symptoms present within a few days of exposure and are quite variable between patients. Parasthesias (numbness and tingling) of the oral region and extremities, generalized itching, myalgias, hot/cold temperature sensation reversal, and dysthesias have been reported. Hot/cold reversal is considered characteristic of ciguatera; however, not all patients describe this sensation. Neurotoxic shellfish poisoning caused by the neurotoxin brevitoxin may also produce a hot/cold dysthesia. Dental pain has also been described following ciguatoxin exposure. Neuropsychiatric symptoms such as anxiety, subjective memory loss, depression, and difficulty in concentrating may occur. More marked disturbances such as hallucinations, giddiness, ataxia or incoordination, and coma have been reported following exposure to Pacific ciguatoxins. Ciguatera fish poisoning is rarely fatal; however, death may occur from complications related to bradycardia, hypotension, or respiratory muscle paralysis if not appropriately treated.
Chronic Toxicity (or Exposure) Human After the initial period of gastrointestinal symptoms has abated, patients may continue to experience chronic neurological and neuropsychiatric symptoms. Feelings of subjective weakness, extremity parasthesias, malaise, headaches, and fatigue may persist for weeks to months. In one study of 12 ciguatera patients, there was no difference between exposed patients and healthy controls on measures of neuroexcitation and neuropsychiatric complaints at 6-month postexposure. Rarely, symptoms lasting for years have been reported; however, these case reports suffer from potential confounding due to other medical or psychiatric illnesses. Regional differences in ciguatoxins may mediate some symptom chronicity; however, symptoms lasting longer than 1 year should prompt evaluation for other etiologies.
Reproductive and Developmental Toxicity The effects of ciguatoxins on pregnancy are not well known or described. Spontaneous abortion, premature labor, and neurological deficits in the newborn have been described in
Ciguatoxin
epidemiological surveys in endemic areas and small case series of pregnant patients diagnosed with ciguatera. It is also speculated that ciguatoxins may be passed through breast milk and the placenta. However, additional case reports suggest normal pregnancy and no adverse effects to the developing fetus following ciguatera poisoning. Further studies and research are needed.
In Vitro Toxicity Data All ciguatoxins bind specifically and with high affinity for voltage-dependent sodium channels in the rat brain. Relatively small chemical differences between ciguatoxin molecules result in significant differences in the affinity for the sodium channel. Ciguatoxins have also demonstrated direct cytotoxic effects on mouse neuroblastoma cells. Toxicity is likely secondary to modulation of voltage-gated sodium channels but may involve other cellular effects. Other in vitro animal studies suggest blockade of potassium channels in cultured rat cerebellar cells.
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exacerbate symptoms and should be avoided. Any type of physical exertion has similarly been reported to exacerbate symptoms.
Ecotoxicology It remains unclear both why ciguatoxins are produced by dinoflagellates and if there are any significant adverse clinical effects of ciguatoxins on fish. Several studies suggest that ciguatoxins may alter the color of scales in barracuda; however, whether this effect occurs in other species of fish or is functionally relevant is unknown. Further studies are necessary to determine the effects of ciguatoxins on fish as it is bioconcentrated along the food chain.
See also: Food Safety and Toxicology; Marine Venoms and Toxins; Neurotoxicity; Scombroid; Shellfish Poisoning, Paralytic.
Further Reading Clinical Management Treatment for ciguatoxin poisoning is predominantly supportive in nature and symptomatic. Analgesics may be necessary for muscle cramping and pain, antihistamines for pruritis, and antiemetics for nausea and vomiting. Advanced interventions including cardiovascular support and vasopressors may be necessary for those patients who experience bradycardia, hypotension, or cardiovascular collapse. Mannitol (20%, 5–10 ml kg 1 over 1 h) is often recommended to potentially ameliorate or reverse neurological dysfunction. Previous case reports and uncontrolled trials have demonstrated a benefit in 60% of cases when given within the first 24 h of the symptoms. Other studies suggest a benefit up to 2 months. Mannitol remains controversial, however, as a clear mechanism of action has not been elucidated and controlled studies have demonstrated no benefit in reversing or reducing neurological symptoms. Proposed mechanisms for mannitol include reduction of neuronal swelling, prevention of sodium channel opening, prevention of binding of ciguatoxin to receptors, or neutralization of circulating ciguatoxin. The ideal treatment, however, for ciguatera fish poisoning remains unclear. Patients who have experienced ciguatera in the past are extremely sensitive to reexposure with more severe symptoms often described. Alcohol, mushrooms, nuts, caffeine, any type of fish, shellfish, pork, chicken, and chocolate may also
Bottein, M.Y., Wang, Z., Ramsdell, J.S., 2011. Toxicokinetics of the ciguatoxin P-CTX1 in rats after intraperitoneal or oral administration. Toxicology 284 (1–3), 1–6. Dickey, R.W., Plakas, S.M., 2010. Ciguatera: a public health perspective. Toxicon 56 (2), 123–136. Dickey, R., Bottein, M.Y., Backer, L., Ayyar, R., Weisman, R., Watkins, S., Granade, R., Reich, A., 2008. Ciguatera fish poisoning: treatment, prevention and management. Mar. Drugs 6 (3), 456–479. Bagnis, R.A., Legrand, A.-M., 1987. Clinical features on 12 890 cases of ciguatera (fish poisoning) in French Polynesia. In: Gopalakrishnakone, P., Tan, C.K. (Eds.), Progress in Venom and Toxin Research. National University of Singapore, Singapore, pp. 372–384. Pearn, J.H., Harvey, P., De Ambrosis, W., Lewis, R., McKay, R., 1982. Ciguatera and pregnancy. Med. J. Aust. 1, 57–58. Rivera-Alsina, M.E., Payne, C., Pou, A., Payne, S., 1991. Ciguatera poisoning in pregnancy. Am. J. Obstet. Gynecol. 164 (1 Pt 2), 397. Senecal, P.E., Osterloh, J.D., 1991. Normal fetal outcome after maternal ciguateric toxin exposure in the second trimester. J. Toxicol. Clin. Toxicol. 29 (4), 473–478.
Relevant Websites http://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodborne PathogensNaturalToxins/BadBugBook/ucm070772.htm – US Food and Drug Administration (FDA) Bad Bug Book Accessed May 1, 2012 http://www.cdc.gov/nceh/ciguatera/ – US Centers for Disease Control and Prevention (CDC) Harmful Algal Blooms Accessed May 1, 2012
Chemical Profile l
Synonyms: CTX 1, P-CTX 1, Pacific ciguatoxin 1 Molecular Formula: C60H86O19 l Chemical Structure: l
Background The ciguatoxins are a group of heat-stable, colorless, odorless, and lipid-soluble compounds with a polyether ring structure. They bind avidly to and open voltage-gated sodium channels with symptoms of characteristic neuroexcitability that may last for days to months. There are 12 known ciguatoxins found in Caribbean and tropical Atlantic waters and 29 reported ciguatoxins in Pacific waters. Ciguatoxins may be found in the flesh and viscera of predatory coral-reef fish from waters predominantly between 35 south and 35 north latitude. Implicated species of fish are predatory reef fish, including Amberjack, Barracuda, Cinnamon, Coral trout, Dolphin, Eel, Emperor, Spanish mackerel, Surgeon fish, Grouper, Kingfish, Paddletail,
Encyclopedia of Toxicology, Volume 1
Parrot fish, Red snapper, Reef cord, Sea bass, Swordfish, and Yankee whiting. Ciguatera poisoning may occur after consumption of these fish. Ciguatera poisoning is also known as ciguatera fish poisoning or ichthyosarcotoxism. Unfortunately, ciguatoxin-
containing fish look, smell, and taste normal, thereby preventing easy identification of contaminated fish. Laboratorybased detection methods (gas and liquid chromatography/ mass spectroscopy) for the presence of ciguatoxins in fish are available; however, they remain labor and time intensive. To date, there are no laboratory tests commercially available for the detection of ciguatoxins in human blood and diagnosis remains based on the characteristic signs and symptoms and on the history of fish consumption. Expanding trade from ciguatoxin endemic areas has contributed to a wider distribution and increasing frequency of reported disease in nonendemic areas where poisoning may be underrecognized or under appreciated. Ciguatera is responsible for the highest reported incidence of food-borne illness attributable to finfish in the United States
http://dx.doi.org/10.1016/B978-0-12-386454-3.00712-0
963
964
Ciguatoxin
and worldwide with 50 000 cases reported annually; however, underreporting is likely in endemic areas. Most exposures are reported following the exposure to fish caught in Pacific, Indian, or Caribbean waters.
Exposure Routes and Pathways Ciguatera occurs after the consumption of ciguatoxic fish listed above, including Grouper, Red snapper, Barracuda, and Amberjack. These large carnivorous and predatory reef fish accumulate toxin after consumption of smaller reef fish, which have fed on toxic dinoflagellates such as Gambierdiscus toxicus and related species. Bottom-dwelling dinoflagellates synthesize ciguatoxins for unclear purposes. Ciguatoxins become concentrated up the food chain, with humans at the top. Contaminated fish accumulate ciguatoxins in the flesh, muscle, skin, and viscera. In Pacific waters, as ciguatoxin moves up the food chain, biotransformation occurs resulting in a more oxidized form of ciguatoxin with increased toxicity. Ciguatoxin is one of the most potent natural toxins known. One pacific ciguatoxin (P-CTX-1) poses a health risk at concentrations as low as 0.08–0.1 mg kg 1 in man. Most fish do not concentrate sufficient ciguatoxin to be lethal to humans. Neither cooking nor freezing can inactivate the toxin. Fishermen in endemic areas may rub fish organ tissue across their gums to determine safety with the sensation of tingling denoting an unsafe fish.
Toxicokinetics Signs and symptoms of toxicity occur 30 min to 30 h (average 6 h) after consumption of the contaminated fish. To date, no study has evaluated the toxicokinetics of ciguatoxin in humans. A rat model using one of the Pacific ciguatoxins (P-CTX-1) demonstrated a peak blood concentration at 1.97 h after oral exposure. Ciguatoxin elimination from the blood was slow with a terminal half-life of 82 h. Ciguatoxin activity was measured in rat liver, muscle, and brain 96 h after exposure. Small amounts of ciguatoxin appeared in the urine; however, the main route of excretion was in the feces.
Mechanism of Toxicity Ciguatoxins have been demonstrated to bind to and modulate the activity of cell membrane voltage-gated sodium channels. Ciguatoxins bind at site 5 on the alpha subunit, resulting in the opening of the channels at resting membrane potential. Sodium influx causes membrane depolarization and spontaneous or repetitive firing of action potentials. In vitro studies using mammalian dorsal root ganglia demonstrated an increased recovery of sodium channels from the inactivated state with resultant neuroexcitability. The influx of sodium into the neuronal tissue results in cellular swelling with decreased conduction velocity and neurotransmission. This excess neuroexcitation is thought to be the etiology of the neurological symptoms often described by patients. Recovery from ciguatoxin binding and modulation may take months to years as new receptors are synthesized.
Acute and Short-Term Toxicity (or Exposure) Human Gastrointestinal and neurological symptoms are most commonly described following ciguatoxin exposure; however, the pattern is highly geographically variable and likely reflects differences in the effects and relative potencies of different types of ciguatoxins. In the Caribbean, gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain are reported to occur prior to the development of neurological symptoms. In Pacific and Indian waters, neurological symptoms predominate with minimal gastrointestinal effects. Nausea, vomiting, diarrhea, and abdominal pain may occur within 6–24 h of consumption of fish with spontaneous resolution in 1–4 days. Early in the disease course, cardiovascular toxicity manifested by hypotension and bradycardia may occur and requires prompt resuscitative medical care. Neurological symptoms present within a few days of exposure and are quite variable between patients. Parasthesias (numbness and tingling) of the oral region and extremities, generalized itching, myalgias, hot/cold temperature sensation reversal, and dysthesias have been reported. Hot/cold reversal is considered characteristic of ciguatera; however, not all patients describe this sensation. Neurotoxic shellfish poisoning caused by the neurotoxin brevitoxin may also produce a hot/cold dysthesia. Dental pain has also been described following ciguatoxin exposure. Neuropsychiatric symptoms such as anxiety, subjective memory loss, depression, and difficulty in concentrating may occur. More marked disturbances such as hallucinations, giddiness, ataxia or incoordination, and coma have been reported following exposure to Pacific ciguatoxins. Ciguatera fish poisoning is rarely fatal; however, death may occur from complications related to bradycardia, hypotension, or respiratory muscle paralysis if not appropriately treated.
Chronic Toxicity (or Exposure) Human After the initial period of gastrointestinal symptoms has abated, patients may continue to experience chronic neurological and neuropsychiatric symptoms. Feelings of subjective weakness, extremity parasthesias, malaise, headaches, and fatigue may persist for weeks to months. In one study of 12 ciguatera patients, there was no difference between exposed patients and healthy controls on measures of neuroexcitation and neuropsychiatric complaints at 6-month postexposure. Rarely, symptoms lasting for years have been reported; however, these case reports suffer from potential confounding due to other medical or psychiatric illnesses. Regional differences in ciguatoxins may mediate some symptom chronicity; however, symptoms lasting longer than 1 year should prompt evaluation for other etiologies.
Reproductive and Developmental Toxicity The effects of ciguatoxins on pregnancy are not well known or described. Spontaneous abortion, premature labor, and neurological deficits in the newborn have been described in
Ciguatoxin
epidemiological surveys in endemic areas and small case series of pregnant patients diagnosed with ciguatera. It is also speculated that ciguatoxins may be passed through breast milk and the placenta. However, additional case reports suggest normal pregnancy and no adverse effects to the developing fetus following ciguatera poisoning. Further studies and research are needed.
In Vitro Toxicity Data All ciguatoxins bind specifically and with high affinity for voltage-dependent sodium channels in the rat brain. Relatively small chemical differences between ciguatoxin molecules result in significant differences in the affinity for the sodium channel. Ciguatoxins have also demonstrated direct cytotoxic effects on mouse neuroblastoma cells. Toxicity is likely secondary to modulation of voltage-gated sodium channels but may involve other cellular effects. Other in vitro animal studies suggest blockade of potassium channels in cultured rat cerebellar cells.
965
exacerbate symptoms and should be avoided. Any type of physical exertion has similarly been reported to exacerbate symptoms.
Ecotoxicology It remains unclear both why ciguatoxins are produced by dinoflagellates and if there are any significant adverse clinical effects of ciguatoxins on fish. Several studies suggest that ciguatoxins may alter the color of scales in barracuda; however, whether this effect occurs in other species of fish or is functionally relevant is unknown. Further studies are necessary to determine the effects of ciguatoxins on fish as it is bioconcentrated along the food chain.
See also: Food Safety and Toxicology; Marine Venoms and Toxins; Neurotoxicity; Scombroid; Shellfish Poisoning, Paralytic.
Further Reading Clinical Management Treatment for ciguatoxin poisoning is predominantly supportive in nature and symptomatic. Analgesics may be necessary for muscle cramping and pain, antihistamines for pruritis, and antiemetics for nausea and vomiting. Advanced interventions including cardiovascular support and vasopressors may be necessary for those patients who experience bradycardia, hypotension, or cardiovascular collapse. Mannitol (20%, 5–10 ml kg 1 over 1 h) is often recommended to potentially ameliorate or reverse neurological dysfunction. Previous case reports and uncontrolled trials have demonstrated a benefit in 60% of cases when given within the first 24 h of the symptoms. Other studies suggest a benefit up to 2 months. Mannitol remains controversial, however, as a clear mechanism of action has not been elucidated and controlled studies have demonstrated no benefit in reversing or reducing neurological symptoms. Proposed mechanisms for mannitol include reduction of neuronal swelling, prevention of sodium channel opening, prevention of binding of ciguatoxin to receptors, or neutralization of circulating ciguatoxin. The ideal treatment, however, for ciguatera fish poisoning remains unclear. Patients who have experienced ciguatera in the past are extremely sensitive to reexposure with more severe symptoms often described. Alcohol, mushrooms, nuts, caffeine, any type of fish, shellfish, pork, chicken, and chocolate may also
Bottein, M.Y., Wang, Z., Ramsdell, J.S., 2011. Toxicokinetics of the ciguatoxin P-CTX1 in rats after intraperitoneal or oral administration. Toxicology 284 (1–3), 1–6. Dickey, R.W., Plakas, S.M., 2010. Ciguatera: a public health perspective. Toxicon 56 (2), 123–136. Dickey, R., Bottein, M.Y., Backer, L., Ayyar, R., Weisman, R., Watkins, S., Granade, R., Reich, A., 2008. Ciguatera fish poisoning: treatment, prevention and management. Mar. Drugs 6 (3), 456–479. Bagnis, R.A., Legrand, A.-M., 1987. Clinical features on 12 890 cases of ciguatera (fish poisoning) in French Polynesia. In: Gopalakrishnakone, P., Tan, C.K. (Eds.), Progress in Venom and Toxin Research. National University of Singapore, Singapore, pp. 372–384. Pearn, J.H., Harvey, P., De Ambrosis, W., Lewis, R., McKay, R., 1982. Ciguatera and pregnancy. Med. J. Aust. 1, 57–58. Rivera-Alsina, M.E., Payne, C., Pou, A., Payne, S., 1991. Ciguatera poisoning in pregnancy. Am. J. Obstet. Gynecol. 164 (1 Pt 2), 397. Senecal, P.E., Osterloh, J.D., 1991. Normal fetal outcome after maternal ciguateric toxin exposure in the second trimester. J. Toxicol. Clin. Toxicol. 29 (4), 473–478.
Relevant Websites http://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodborne PathogensNaturalToxins/BadBugBook/ucm070772.htm – US Food and Drug Administration (FDA) Bad Bug Book Accessed May 1, 2012 http://www.cdc.gov/nceh/ciguatera/ – US Centers for Disease Control and Prevention (CDC) Harmful Algal Blooms Accessed May 1, 2012