슬라이드 1

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1 [3.9] 곰팡이독소중독증 Mycotoxin : 곰팡이가생산하는 2 차대사물, 유독성 비병원성곰팡이가생산하는비단백질성의저분자화합물로서항생물질과는구별된다. 장독소도아닌것이특징 발암물질에속하는것이많다 세포신호전달계교란, apoptosis 간, 신독성 사람이나동물에질병이나이상한생리작용을유발 Mycotoxicosis: mycotoxin 섭취에의한질병 1. Mycotoxicosis 의특징 탄수화물이풍부한농산물이나곡류에많이오염됨 계절과관련 Penicillium, Aspergillus 속에의한사고 : 봄철 ~ 여름철에많음 Fusarium 독소균에의한사고 : 가을 ~ 겨울철 ( 또는한대지방 ) 에많음 감염형이아님 ( 직접전염되지않음 ) 항생물질이나약제요법을시행하여도큰효과가없음 History 16C: 유럽, ergotism: Claviceps purpurea 오염보리빵 17C: 일본, yellow rice disease: Penicillium 오염쌀 20C 초,: 러시아, ATA:(alimentary toxic aleukemia) : Penicillium 오염곡물 1960 : 영국, A. flavus dhdua 땅콩, 칠면조집단폐사

DEFINITIONS : Contaminants in diets 'Contaminant' means any substance not intentionally added to food which is present in such food as a result of the production (including operations carried out in

2 DEFINITIONS : Contaminants in diets 'Contaminant' means any substance not intentionally added to food which is present in such food as a result of the production (including operations carried out in crop husbandry, animal husbandry and veterinary medicine), manufacture, processing, preparation, treatment, packing, packaging, transport or holding of such food, or as a result of environmental contamination. Extraneous matter, such as, for example, insect fragments, animal hair, etc, is not covered by this definition. «Toute substance décelée dans un lieu ou elle ne se trouve pas normalement» Commission OSPAR. «Substance indésirable se trouvant dans une matière et qui a une incidence sur la possibilité d'utiliser ou de transformer convenablement la matière en question» CCIPP (Canada)

3 Contaminants in diets Heavy metals Pesticides Radioactive components Phyto-oestrogens Mycotoxins Bacteria, Fungus, virus. Medicines Others (acrylamide, melamine, )

4 Number of scientific references Mycotoxins Number of scientific references per decade when launching a search with «mycotoxin» as a keyword. Source Pubmed database : review original papers Decades

5 Mycotoxin 의분류와종류 현재 100 여종의곰팡이독소가알려져있음 발견균주에따른분류 장애가일어나는부위에따른분류 1) 식중독유래 Mycotoxin 식중독원인식에서직접분리추출된물질 aflatoxin, fusarium 독소군, patulin maltoryzine, sporidesmin, psoralen 등 2) 오염균주유래 mycotoxin 오염된곰팡이를분리하여인공적으로배양 => 실험동물에의하여독성이확인된물질 황변미독, fumonisin 3) 보존균주유래 mycotoxin 식품과는직접관계는없지만 mycotoxin 의생산성이있는곰팡이와분류학상가까운균주를검색하고그대사산물의독성을실험동물에서분명히한것 1) 간장독 (hepatotoxin): 간경변, 간종양, 간세포의괴사 - aflatoxin, sterigmatocystin, rubratoxin, islanditoxin, luteoskyrin, ochratoxin 2) 신장독 (nephrotoxin) : 신장에급성또는만성의신장염 - citrinin, kojic acid 3) 신경독 (neurotoxin) : 뇌및중추신경계에장애 - paturin, maltoryzine, citreoviridin 4) 기타 - sporidesmin, psoralen : 광과민성피부염물질 - zearalenone : 발정유인물질 ( 돼지 ) - salframine, fusarium 독소군 : 조혈기능장애물질, 조직출혈유발

6 간장독소 신경독소 독소의종류독소생산균주피해동물중독증상 Aflatoxin Ochratoxin Islanditoxin sterigmatocystin rubratoxin 함염소 peptide luteoskyrin Citreoviridin Paturin Cyclopiazonic acid Maltoryzine 신장독소 Citrinin Kojic acid 피부독소 Sporidesmin Methyl psoralen 기타 Fusariogenin Zearalenone Slaframine A. flavus A. ochracepis P. islandicum P. citreoviride A. clavatus P. cyclopium P. citrinum A. oryzae Pithomyces chartarum Sclerotine scleotiorum F. sporotrichoides F. graminerum Rhizoctonia sp. 척추동물전반소사람 사람, 고양이소돼지 사람 소사람, 가축 사람돼지말소 간장손상, 간암지방간, 유산간출혈 중추신경장해뇌신경장해경련 신장염 광과민성안면피부염광과민성피부염 조혈조직장해발정증후군설사, 유산 곰팡이독소의특징 곡류, 목초등의특정한식품이나사료의섭취가원인 원인물질이곰팡이에오염되어있다. 식중독발생은계절과관계가깊다. 곰팡이독소중독은전염되지않는다. 항생물질이나약제요법을시행하여도큰효과가없다.

7 표 3-6 오염곡류에서알려진 mycotoxin 의종류와독성 Mycotoxicosis 균명 Mycotoxin LD50[mg/kg] Alimentary toxic aleukia Fusarium tricinctum Sporofusariogenin Cladosporium epiphtylum Epicladosporic acid Fagicladosporic Cladosporium fagi acid Yellow rice toxicosis Pen.islandicum Islanditoxin 0.3iv.(mouse) 0.47 sc.(mouse) 6.5 oeal(mouse) Luteoskyrin 6.6iv.(mouse) 147 sc.(mouse) 221 oral(mouse) Pen.rugulosum Rugulosin Pen.uriticae Patulin 10 sc.(mouse) Pen.citrinum Citrinin 35 sc.(mouse) Pen. motatum Xabtgicullin Pen.citreoviride Citreoviridin Asp.fumigatus Fumahagillin 800 sc.(mouse) Glutoxin sc.(mouse) Helvolic acid 400 ip.(mouse) Asp. terreus Terreic acid iv.(mouse) Vulvo-vaginitis in swine Fusarium graminearum Zearalenone Gibberella zeae Moldy corn toxicosis Asp. flavus Afaltoxin 0.36 oral(duckling) 5.5 oral(rat) Aflatoxin 0.78 oral(duckling) Aflatoxin Aspergillic acid 150 ip.(mouse) Aspertoxin Pen.rubrum Rubratoxin 400 oral(mouse) 2.6 ip(mouse) Pen.cyclopium Cyclopiazononic acid Asp.ochraceus Ochratoxin A 0.5 oral(mouse) Trichoderma viride Trichodermin Trichoderma roseum Trichothecin 300 oral(mouse) 6- Hydroxyrosenolactone Fusarium scirpi Diacetoxyscirpenol 7.3 oral(mouse) 0.75 ip.(mouse) Fusarium tricinctum T-2 toxin 4 oral(mouse) 4-Acetaminde-4- hydroxy-4-butenoicacid lactone 44 ip.(mose)

8 Aflatoxins Trichothecens Ergot alkaloids Fumonisins Others B1 G1 M1 B2 G2 M2 A B Diacetoxyscirpenol Toxin T2 Toxin HT2 Amide Clavine Peptide B1 B2 Ochratoxin Zearalenon LSD Ergine (LSA) Deoxynivalenol Ergoline Nivalenol Ergotamin Fusarenon Ergométrin

Aflatoxin 발생역사 - 1950 년영국에서 10 만마리이상의칠면조떼죽음 - 수입된땅콩류의 mycotoxin 에의한급성간장장애 Aflatoxin 생산균주 : Aspergillus flavus, Aspergillus parasiticus 종류 : 18 종 (B 1, B 2, G 1, G 2, M 1, M 2 등 ) 형광유발 : 청색형광

9 Aflatoxin 발생역사 년영국에서 10 만마리이상의칠면조떼죽음 - 수입된땅콩류의 mycotoxin 에의한급성간장장애 Aflatoxin 생산균주 : Aspergillus flavus, Aspergillus parasiticus 종류 : 18 종 (B 1, B 2, G 1, G 2, M 1, M 2 등 ) 형광유발 : 청색형광 -aflatoxin B 1, B 2 청록색형광 -aflatoxin G 1, G 2 오줌, 대변, 우유에서발견되는것 : aflatoxin M 1, M 2 균특성 세계전역의토양 ( 주로열대, 아열대지방 ) toxin 생산능력은환경의변화에따른차이가많음 최적생산조건 : 수분 16%, 상대습도 80-85%, 온도 주오염식품 : - 쌀, 보리, 옥수수, 밀등의곡류독성 강력한간장독, 강력한발암물질 식품위생상가장중요한것 : aflatoxin B 1, M 1 ( 강력한발암작용 ) B1 > M1 > G1 > B2> M2 G2 DHFF, THFF 부위가특유생리작용부위특성 - 메탄올, 아세톤, 클로르포름에용해 로가열해야분해 ( 일반적인식품의가공살균처리로파괴?) 규정 국가규제량비고국가규제량비고 WHO/FAO 한국 20ppb 10ppb B 1, B 2, G 1, G 2 총량 전식품 B 1 곡류, 두류, 땅콩, 견 과류및그단순가공품 미국 20ppb 총량, 식품과사료 영국 5ppb B 1, 견과, 견과제품 일본 10ppb B 1, 전식품프랑스 10ppb 총량, 전식품 중국 50ppb B 1, 쌀, 땅콩, 옥수수등호주 5ppb 총량, 전식품 예방 - 곡류의수확후건조등저장조건에유의 : 상대습도 70% 이하로유지 (aflatoxin 최적상대습도 80-85%) 옥수수, 밀수분 13%, 땅콩 7% 이하 (aflatoxin 최적수분 16% 이상 )

10 아플라톡신의종류

11 Sterigmatocystin 자연계에널리분포 Aspergillus versicoler, Asp. nidulans의대사산물 화학구조는 Aflatoxin과비슷함 급성독성은약하나발암성이있음 (aflatoxin의 1/250정도 ) 간장과신장독 ( 동물에서간암유발 ) 곡류 ( 밀귀리치즈커피원두등 ) UV하에서암적색 비교적낮은온도에서도생육함

12 황변미중독 유래 발생 : 쌀수분 14-15% 이상 곰팡이생육 good 독소산생곰팡이 쌀이황색으로변질 황변미 (yellow rice) toxicarium 황변미 ( 대만쌀 ) Penicillium citreonigrum 의대사산물인 citreoviridin ( 신경독 ) 1937 년이후쌀에서만문제 상행성마비 호흡장애, 혈액순환이상, 경련 진행시호흡마비로사망 만성중독 : 빈혈 자외선, 햇빛조사 (2 일간 ) 에불활화 kakuda 황변미 ( 태국쌀 ) Penicillium citrinum 의대사산물인 citrinin ( 신장독 ) 1951 년이후정미한쌀, 빵, 염지햄, 밀, 귀리, 호밀 UV 하에서레몬빛황색 급, 만성 nephrosis Islandia 황변미 ( 이집트쌀 ) Penicillium islandicum 이생성하는 luteoskyrin, erythroskyrin, islanditoxin, cyclochlorotin 에의함 1948 년이후쌀, 소맥, 수수, 후추 ( 간독성 )

13 황변미중독을일으키는 mycotoxins

14 Rubratoxin Penicillium rubrum의대사산물 P. purpurogenum도산생 A, B의 2종이분리 여러가지장기의출혈과간장및신장, 폐조직장애 LD 50 = 2.6 mg/kg mouse, IP. 400 mg/kg mouse oral. 발암성은없음

15 Trichothecene 계 Mycotoxin Fusarium 계에서분리 diacetoxyscirpenol T-2 toxin( 화학무기생산에이용 ) nivalenole, fusarenon X, vomitoxin Fusarium 계가아닌것에서분리 tricodermin, trichothecin 등 DNA 및단백질합성저해에의한조직손상 장관비대출혈, 흉선의위축출혈, 간장및비장의비대, 여러장기의괴사 오스트레일리아, 미국등에서의소다리저는병 (fescue food) 원인물질

16 식중독성무백혈구증 (Alimentary toxic aleukemia, ATA) Fusarium poae, Cladosporium epihyllum, F. sporotichioides 등 기온이매우낮거나강설량이많은기후조건에서도잘번식 sporofusariogenin, epicladosporic acid, fagicladosporic acid 주로겨울과봄사이에구소련지역에서치명적으로발생 구강및소화기에이상 장기간섭취시조혈기능장애 : 백혈구감소, 임파구증대, 혈액응고시간지연등

17 Zearalenone Fusarium graminearum F-2 toxin 또는 FES (fermentation estrogenic substance) 이곰팡이에오염된옥수수, 보리, 목초에의하여발생 Pig estrogenic syndrome : 돼지발정증후출현 (estrogen 양작용 ) 사료중 1-5ppm의함량으로외음부종창및탈출, 유방및자궁비대

18 Alternaria toxins 사과, 토마토, 블루베리, 곡류등 Alternaria 속 : A.citri, A.alternata, A.solani, A.tenuissima 를포함한여러종 Alternariol, alternariol monomethyl ether, alternuene, tenuazonic acid, altertoxin-1 등. Allergen (hey fever, 과민증, 천식 ) 면역억제환자 (AIDS ) 에서기회감염

19 Ochratoxin Aspergillus ochraceus 등의 2 차대사생성물 ( 옥수수, 두류, 곡류향신료, 커피원두, 염지햄등 ) Ochratoxin A( 독성이가장강력 ), B, C 의 3 종류 UV 하 : OA( 녹색 ), OB( 청색 ), OC 간장 ( 지방변성, glycogen 합성효소저해 ), 신장독성 면역독성 OA: 신경독소도인정.. Ochratoxin A 의 LD 50 = 0.5 mg/kg duckling, oral Ochratoxin B, C 는 A 의 1/1000 이하

20 Patulin 곰팡이에감염된과일에주로생성 Pen. patulum, Asp. Calvatus 쌀, 밀, 콩, 간장, 미역등여러식품에서분리 Pen. lapidosum 과 Byssochlamys nivea 는내열성 통조림, 병조림식품에서도발견 동물에서피하육종 발암물질 뇌및중추신경계에출혈반형성 Penicillinic acid P. puberulum 포함한많은 Penicillia 속, A. ochraceus 그룹 Patulin 과유사한생물학적특징

21 Fumonisins Fusarium spp. (F. moniliforme 이다량생산 ) 옥수수와기타곡류와깊은관계 FA1 ~ FA15 사람의식도암과관련 동물의간병변 말의뇌백질연화증 돼지의폐수종 쥐간암 Sambutoxin 1994 한국보고 Fusarium sambucinum, F. soysporum 썩은감자와깊은관계 쥐의위장에서출혈 동물의식욕감퇴, 체중저하

22 광과민성피부염물질 - 햇빛조사에의하여피부염등을일으키는물질 - psoralen계화합물및 sporidesmin류가대표적 - psoralen계 Sclerolina sclerotiorum ( 샐러리의홍부병원인체 ) 에서유래 이병원균오염샐러리수확시접촉한사람이일광을쬘때피부염유발 - Sporidesmin류 Sporidesmin bakeri 또는 Spo. chartarum ( 건초등에기생 ) 가축의안면일광피부염의원인물질 반추동물 : 간장장애, 체중감소, 황달, 광과민증, 2차적으로안면습진

이명, 무기력, 지각이상등 임산부에게는조산및유산을일으키기도함 만성중독 : 말초혈관의순환장애 : 사지, 코, 귀의괴저 독성분의주성분 : 맥각 alkaloid

23 맥각중독 맥각 alkaloids 의종류 Claviceps purpurea 균핵 (sclerotium) 을맥각 (ergot) 이라함 호밀, 라이맥, 보리. 에서잘번식 흑청색으로변색되면부서지기쉬움 맥각 : 근육수축 ( 자궁수축 ) 일으켜의약품으로사용 양이많을경우독성물질로작용-> 맥각병 (ergotism) 소화기계통의장애및두통, 이명, 무기력, 지각이상등 임산부에게는조산및유산을일으키기도함 만성중독 : 말초혈관의순환장애 : 사지, 코, 귀의괴저 독성분의주성분 : 맥각 alkaloid Ergotamine Ergotoxine Ergometrine 곡물중에맥각이 0.5% 혼입되면독성을보이며, 7% 이상은치사량 곡물중맥각의허용량 : 소련 0.15%, 캐나다 0.2%, 미국 0.3% 미량으로환각작용유발

Many alkaloids can be purified from crude extracts by acid-base extraction.

24 Alkaloid An alkaloid is a nitrogen-containing naturally occurring compound, produced by a large variety of organisms, including fungi, plants, animals, and bacteria. Many alkaloids have pharmacological effects on h & a. Many alkaloids can be purified from crude extracts by acid-base extraction. While many alkaloids are poisonous, some are used medicinally as analgesics (pain relievers) or anaesthetics, particularly morphine and codeine, and for other uses. Ephedrine Caffeine

25 의약품으로사용되는 toxin Tetrodotoxin - 사람의신경과근육세포표면에있는 Na + 의세포내로의유입방해 신경전달방해로호흡마비 - 극소량의사용시특정신경마비 신경치료제로활용 - 일본 : 19 세기에이미진통제등의주사약으로개발하여발매 - 최근에이즈환자, 관절염환자, 마약중독자, 뇌질환자등에활용연구 맥각중독유발 mycotoxin - Claviceps purpurea - 자궁수축, 환각작용 보툴리눔 toxin - Clostridium botulium - acetylcholin 유리저해 신경마비 - 보톡스 : - 안면경련 - 뇌성마비환자 - 눈가의주름제거 - 통증클리닉

26 ** Exposure in Contaminated Environments Beginning in late 1980s scientists began raising the issue of possible inhalant exposure Mycotoxins are not volatile but they are present in fungal spores In contaminated indoor environments, people may be inhaling hundreds to thousands of fungal spores per hour If the spore are toxigenic, risks may occur Indoor Fungi Indoor spores generally reflects outdoors unless there is a source of contamination Many different types of fungi occur Most common genus is Cladosporium - just like it is outdoors BUT Penicillium and Aspergillus often exist at higher concentrations indoors Stachybotrys has received most media attention over the past 4 years

27 Cladosporium Common fungal genus occurring both indoors and outdoors Most abundant outdoor spore type with a worldwide distribution Normally exists as a saprobe or weak plant pathogen Spores are known to be allergenic These fungi are known to cause skin lesions, keratitis, nail fungus, sinusitis, asthma, and pulmonary infections.

28 Penicillium and Aspergillus Small spores passively aerosolized when spore clusters disturbed Spores extremely buoyant, remain airborne for extended time 3-day old Aspergillus colonies. Clockwise from top-left: an A. nidulans laboratory strain; a similar strain with a mutation in the ya marker gene involved in green pigmentation; an A. oryzae strain used in soy fermentation; A. oryzae RIB

Produce VOCs Well known allergen (can cause hypersensitive

29 Penicillium One of the most common soil fungi in natural environment Over 250 species Some species produce mycotoxins Produce VOCs Well known allergen (can cause hypersensitive pneumonitis, allergic alveolitis, and asthma in certain individuals.)

30 Aspergillus Also common soil fungus and cause rot of stored grain Over 150 species Well known allergens Several species form mycotoxins Some species can grow at high temperatures Several species can cause human infections of lung and hypersensitivity pneumonitis

Stachybotrys Soil fungus in nature Commnly called black mold Commonly found

straw baskets, and paper materials Spores in slimy mass May produce potent

humans are dermatitis, pain and inflammation of the mucous membranes, burning

31 Stachybotrys Soil fungus in nature Commnly called black mold Commonly found indoors on wet materials containing cellulose, such as wallboard, jute, wicker, straw baskets, and paper materials Spores in slimy mass May produce potent mycotoxins Thought to be allergenic although little is known Common symptoms in humans are dermatitis, pain and inflammation of the mucous membranes, burning sensation in nasal passages, tightness of the chest, cough, nose bleeds, fever, headache and fatigue.

33 Health effects from airborne exposure Clinical studies not completed yet Possible correlations in contaminated buildings but no experimental studies with human exposure Animal studies suggest effects of respiratory exposure important Possible effects: immune suppression, rash, headache, fatigue, sore throat, pulmonary hemorrhage (in infants) We need more research

슬라이드 1

슬라이드 1 5 주차 3.4 곰팡이독소 (Mycotoxin) 식중독 1. 아스퍼질러스 (Aspergillus) 속 2. 페니실리움 (Penicillium) 속 3. 후사리움 (Fusarium) 속 4. 맥각독 (Claviceps toxin) 3.4 곰팡이독소 (Mycotoxin) 식중독 곰팡이독소는곰팡이가생산하는 2차대사산물로서사람이나가축에질병또는생리적, 병리적장애를유발하는물질