難分解性有機フッ素化合物PFOS及びPFOAの毒性学的研究

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Title

難分解性有機フッ素化合物PFOS及びPFOAの毒性学的研究(

_{内容の要旨(Summary) )}

Author(s)

河本, 光祐

Report No.(Doctoral

Degree)

博士(獣医学) 甲第328号

Issue Date

2011-03-14

Type

博士論文

Version

none

URL

http://hdl.handle.net/20.500.12099/36613

※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。

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jES*jB3? &32 * B] 4@ fis t*i (5EBi) 5RB;i*EF#3 2 _8% 5FBR2 _3*3,q 1 4E] JB3?1kRRu# 3 _## 1 Qi%j 3*%gA B;_'B%8fgE$1 # BiJB+*4t jES*JB+

#J<5)###* 7.y #1b%4bpFOS&tFPFOAe) %i4:*B9mgE

j=i jE S jc * 6ui #B;%iEj(* 6[ji i S A _JB3? 6rli _3k#Bi I *JB3? 6(li _{d& j>} A _JB3? # i* a i # ]* * ]i i i# Sp A i # *[J PA * E] i f% T El i a i2 * 9f * SL ;8 3t a) _F∼ _* 0) _S E

PFOS (perfluorooctane _sulfonate) i:PFOA _{(perfluorooctanoic}

acid) Gi.I55iffJr*1f jq k3*-?#5iiASf&o)i&7 y #1b%4bThb D , #**8=h,U IT##8=Sv,fjE,J,Jr&k,j% L, fh

ER&4iTChn#*75%bS#% ShTb,8. _=h 6 8j:#4b$5%*#JS!Jqit2 _{2flE=i J3T4*JQ,} i=

SJt*1fB3kSf _%&=+I i bS#%5hTU,8bS, ∼?%41#*f%%L%Lii*Jrk8=Lqa#%Sj:f5 bT,j>tiV 'o _i _I

Th*#gE-eli PFOS jb.i U( PFOA _{D1*Wif41#SJB%L&12i*JrBkPA} _{6 75,8=+}

8 _{i i b8=,} _{#fEfE4h8=#1aJ%*48=-3UIT*id+8} _M9Th, _i%*fE4h7fhb8

yht9 U A,> jb'itF) FAB 1= i bi=AIEj9Bqt29S*#4bThba 5; _,y I,b8V,Ej:? 9A kjqV,TufO)*-#

k11J3f=.

1. PFOS _n'} _{9 U} _{A-Ji=h'81a1*#i^j1#SJh}

yhh9 U A.>8= PFOS i PFOA kPja& Lf= i I _a, PFOA _{fiiK.&^ji#i=,%3g*iP&jiktiblJ'f=b,;,} PFOS _{lj:i&ABriaff7*}_i _U' ₅_{A#tiiKf7*11&k$l} _%kE= _Lf=. _yh'_{9 U Ju>F3:kgB&Pq}

ca2'#&n* j]D8=j:

I,T1&i&3gf7*kli5 I i bS*n 6hTU,8f=b, Pros _0),T3*t L,T#PB&Pg _ca2'ikgLfe) 9BhD*k8B&F5 _{ca2'n5iRJr&k#ba} I _i _bS%k _6nf=. _i _=7:A, _{#F]B&Pqca2+a)gjqf*E=#+}

a PFOS _{a)Bf#8=-?U,T,} Triton #mB&fjlh))I,kjqu,T*2J Lf=o *ffh)i,8j:#F]h&#St LTO)

JrB5fki&* L t3:bS 6 bBR^jlg18=ielftf#%0)qR#f#k## L,f= b 0)7fhb 9 , %0)Bf,i

11g!j]Gj:9L#e)ca2+i&Lfi=i I? T*fJ4*5 i18o PFOS 8j:, Triton *mB&ff'-/i,T>B&4i# i gLijf

Ca2'#BE i _{nF*lr#,8=,%gkji.kiB,} _{#M&Pq ca2'n#j&rB8=B&6gk&8f} i ij:V,_I _i _bt;,j%_{5 hf=.}

i:f= lO _{#0)5Ff5.#Jr*#[lo)E*P%%1fjE} _i _BR41#L=#+ _a _%B4iP_kit:**=H _Lf=#A, _n*P%%

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i 8 _##Abb ti _{Ca2'iEi^bt;JiRW7?1i71hU} ,_i _U, ₅ _I _i _b';,j%PKh5 hf=o

rEEJ!;5iL4=]gfJ*Bi]*-i+8=3b'U'

T, Pros _Ej:W4=#o)./ 9 i)J>,> _tQdilthkTTrB Ca _{91i,*,/I, (VGCC) %#f=fxu'*#'25%#0)}

f5%8= 3 fEIJr&0)hi1&#1k&$l % kE= L]i.. 3i lt Pros 8=

cEJ3 T1&iaiiff7*&*+W4i8RT18j:ff #iEIibSR. 6nf=b';, #.5%_1#-C.(i:i%dWEB:1iJP1&i&igf7*Ei5ibhti75,J3 f=. 5 6 L=, Pros Ej: voltage-clamp _{-#tlLt=TT.0)F)qb}5 Ca _{'EEiEfE=#4iP%Skii,} VGCC i:-LEfEff,r&1ELTEiU'7bu '

I i A;'i%5h7-I. _{,/ 9 U i.>j3Lla} 3 _{fE]Jr&0)BS'gE15i#1t:Eija7E,r&kbI?f=*u'#5%2651yjT,} /i,0)7fJr&1E8=

cEJ3T bf=6 Sh8--*b1;*p 6hTU,8. Lf=i)1;J3T Pros 8=i 812iaiaff7*Ej: VGCC _{ktE4#.IfJr&1E+a} _I _{i C=i} _a _bo)TCli+i _<

, *u#522651yjT,)I,75,60) Ca2'm^8=i 8

ARLj)f5bSn%to) VGCC _{&=0:Bq8=.7fJr&1bL,} _{Ca2+.#L^kSt %&=+I} 2:b';JF,&7:hb8 t* P&5hf=.

2. Pros _e)} _5h-A _{8=jb'81ai*j%J<ff#*Jr&}

pFOSjS i tWFOAk }

i1'*

_L=96FSFp5B%k L, _{%0)11#8=#+8J%ZB&&Bk*-#} L,flo Pros-C>8j:

BEFk5f#k, _{4&i&iifiik &bLj:1't2}i+, #J4p tfL#Rff&n,21EbS&*5hf=o _-i, PFOATlj:

igf7*^j1&0)#1b8j:i5ii A, i.1A 6 YLii, D@-3i 6hf=qZ#-TA%b ##&5E#BE1+hJfTCh 0)&RJ 6 nTh1 9 , 5EtB$0)#*ABbFuEVeT>b8 i 3%* SYt,f=.

3. PFOS ₀₎₇ _y _{I,8=hlLla##i^11#*Jr&}

iPBfgE8=33,V ,T, PFOSe)*FKp&J5-8= _ctD , &%.#*fJ,#8= i a5AFLEiJr&rS#ibS7.y I,Th-5Ph

a 6hTU,a bS, PFOATh83:3#hb E,nfj:i),-3f=. _{PFOS83:#LJ7iWzFJr%T^%*Jr&bii-a} I 2:i),6,

i na#BEi),-?A,gF,5o)FB5aS-Ch=0)i: 5 tf*f%bSST %&= Shab,kPB 6b,8=i-a I _{i fj:i} fiff&BiThb8o %e)T=b*mgE7?1j:, 0, 2, 8, 32b'itF>l28 _{ppmO)PFOSk#.r&WistarViR5?} y Ttkl35AP,5tR*Btji. LT=. 32J5-#FRqq,, -A21i#8=/#1t:tip. 6YLi!, 32 _{ppmnJfO)#7?1j:}

iEi%t#*u#8=#L,T bli&e)/#1t:bt;A6ht}b"f=. L75,L128 ppmO)#Th8j:, #6iA#7F$ 8=6PSEP5EEO) 7 ,y I,bSiS%.&*rlt#8= i _{J3T5&FLELi4iFgE@kSt} 5 kE= L, I nFS.5,Thn&1mos32

%%8i338 _mg/kg-Thb 1 T=. _PFOS*E]#i p ]2jiO)*-#-elj:250 _{mg/kgnj_tO)PFOS32jii&} 8=rF]1#

a)rs@bSB. E,hTja- D , *iWgEO)32ji%8j: =n i i5V11qLE.T>bJ3T=o 3j=, l3iAFpqfR6#32J5i=

b, 818%Lhj2jij%8=#i-8kR#q,a)PFOS#Lfo)Srl%fj:, i5Bg& n ]2J58=h'81a%1l% i f&bT# 1nJL,T=1@k* Lf=. =tL 6 a),#B%fi, 5&tEJr&rS@k$1 %#=1BIBO)PFOSiBiLEbS, ]2ji#/ARB78= iqb 6frWi&7:hb a I i:%,j%P& LTU,flo {fi3, _{BB40)mTi575,iA#J**-i47?13:,}j<BIBh' i: Uth/Jt B#0)1*WfE#PB&JP9h1)7#,PB& 8=#1b8j:a. 6 YL+fbi.J3 f=. BIBO)1*#7it#tF]BB8=ib'V'TCa91 y 4,)I/7516

a)ca2.R^&S(%#=+NMDAbS, rs@##1fRk#+a I tbSh]6h-C"8o ikkBo)-i 5 8=

pFOSbSyN'9 U.h->7fhCaiEE^%SI%k=+I tASPB 6b,i tf-3TB D , 9 y TtO)1*#i#mB&t=ja'

81a _{Ca2+#kE,a),#1t:b1;pFOS8=}i 8 5&Fa.r&rs@ 2:.l3Fjfc< F*lb-3 T V,₈ _q#t:,rfEbS5%_{i 6} _hf=o

4. PFOA _a),}9 ) A,>, } _{5h)*hlitF?9R8=3SL18L&1ii%JF*}

DNA _iAi5t3:Comet assay LEI:J3T*!JL,f=. %0)J#A, PFOS 0)PBE8=i D '}9 1)A-)0)

DNA _{IA@8=2EltSj:3i} _{6nfj:75,J3f=b;,} PFOA _0)RB&&8=i D _{,i 9 u}A->b'iVh} 5h'*o)fu¥1tBf E#-ChDNA IAig-a)#%fftuRA';=#hb E'YLT=o 3:f=, 120 _mg/kg 0) PFOA k#i4: ICR 7 _9Ai= 3

E]FRqii*#L& R ]2ji+a i , BfBE&-ChDNA &i%ntunb';=iEhb 6YLf=o =h 60),#Ai), E)

PFOA 8j:

J5,4=4=%, &*, _F#<'4L#4htJ=*kRJf4=4h8=#L DNA _fAi5kS( %k=+I i bSPA 6b,i tj:I,

f=. _.nfJr%&b## _(ROS) jbl

cttF>#1tBb DNA IAiSe)fBr%rChb a 8-hydroxydeoxyguanosine (8-OH-dG) e)&fJi&,}9yU J>->t } _{5>L*Th411f=#A,} _f*%-eh PFOA 8=i: 8 ROS _0)tuDbS

A6YLf=bS, 8-OH-dG 8=8j:/#ilEi)S3i6htib"flo 3:f=, _{,}9 U J>:>8=bt#1E#u7?hba}

glutathione (GSH) i PFOA %WF$8=BBaSLT=t =b, PFOA i=i:a ROS 0)9uDti GSHrf7Ef

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fBi&to)j=f=8JSEq-eliti < , =31t Ej:Bug)rjifSi)1;#7Ei-8I i b';*P25tlB5hf=.

ut*wgE8=i 9 Pros i PFOA _{Ej:i.qL%Bb8=i5bT#LnJ} L,Tb,ff AS 6, %n%hYL1*#Tifli# SJr&t3&1fiSJr&t U, _{5A7ba*Jr%i:i+8} I tASPB 6Z),i {flf=. 3:T=, PFOS jali:tFPFOA

a),adgE3:#*4=4h71ba.i 9 l)J>,>*} 5>>*8=b2k.A:I i:bSP^ 6b,i Jf 9 , 4=Tjr#-tO)#

#bSR5i% i n7T=o

* 2E a 5E 0) i B

PFOS (perfluorooctane _sulfonate) i PFOA (perfluorooctanoic _acid) bj:5ii5 fEJr*1fB] k#-?#L^iASJr4:iA 7.y _#1b%4h _{a)+taiT> A} 8 o *m:*n-ChEi##i41#*Jr& i

3&12iSJrfEk1*51 L f=Q

1. _'}9 _{U Jh->0)L#*Mi&}

PFOA i PFOS n 5 G@%o)*75S,}9 U _{i.Ji:4&L&iLBf*5%f=o} Pros Ej:yh'9 1)i-J a) Triton _{fj1∼')V8=jb'V} _,TBa11# i 9[ilR_ca2'i*& i 0)1qr#,8=/%4!BkjikffA'J3 f=. #J& _{0)5?f5ffJr&#[JO)*h35RBSP%$1fBj} i _{,i 9 U} J>_,>0)41#8=#-T 8 1fjq K8j:LqLfJrfE bSt2i),1 T=o Pros 8j:gf4=#0),i 9 1)i _-> _i _*taIBhk#Jr&Ca _{31i,jT,}V%#k=7Bu'*jfe#}

2gA*e)f5%8=1bJB3?x*ji3lTg?[S*rJ,#F$8=A E)h8 i15i#1b& ST % A I Lf=bS, #&#ta15Z Ei PFOS _L=n*#hb 6hfT=. Pros Ei _{voltage-clamp} F$0)PqP]% Ca #Eaf}fL8=B!3"@kjik fib,J3 T=. _Lf=bSI T, PFOS 8=j=_{84&i&B:f*R8j:*ut#?R%51y} jT,)I,8=3:8B%J{Dii5bSJm

%te)%I5thk#Jr& Ca _{91-yjT-/I,kffJr&1b}L,, Ca iR^kS[ %&=-T= i bSJ5Bgve)A 8

t*P& 5hf=.

2. } 9L'*o)i*#iff#ST&

PFOS _{8j:jt 5L"A} _{8=BkE]iK5Tf*t@i&3i#*t} _AbLll'ff _{t'1nL#*Mi#n/#1bkSr} _{5 k=}

L,f=AS, PFOA _{TC,Ej:R:tF$0)#q*ABglTR4*ugLo)#1Etj:82} i AJ if>A6htj:A,J3 to 3. 7 ,y I,0)i*#fEE4f#&TE*Jr&

EP5%nL3ji L,f=J;XWO)3S*i=i3V,T, PFOS 250 _{mg/kgJZAtO)5iW#i} D &J5120)A %i&*F]t&8= i -3 T 7 1y Tti=5&f?Fr&rS@bS=#^* 6hT=bSpFOA-e13:#hb 6htfA1-3 flo *

m4ErCliPFOS% 9 ,y h i=13i@Fp5iA6E]2ji*8=Bi%#*u#k11J3 f= i I a, &Lh#ji%

338 _{mg/kg-e>5&Fa.FtBTs@kST} i k= L,flo 3:T=, _{13i@]2%^i&n*B%%8=#+8B'BPg} npFOS#BEbESi*F#ffE P ]2jiFS i _hjfu,1ik* LT=.

ct-3 TBh'8=blL1 8PFOSO)%*Jr&bS lit5 hf=o tj:b'BIB8=3*]5,iA#JB3?B9,#1t8j:3i6 YLtfb,-3 f=.

4. _'}9 U A,>, } _{5ht*jSit^+?9R8=ib'81aiE12i*JrB}

DNABii%tj: Comet assay i=iJ3T*51L,f=. %0)#APFOS Gi'}9 U A,>n DNA k

]BigLtfb,-3f=bS, PFOA tiyht9 U A,>, } 5hlj70)#.gttBfB#33'itF}7 9RnBfB#0)

DNA i:#,i Lf=o yhh₉ U i-J i } 9hh*-ehPFOA i=i ai%Jr**##nt*hpbSja E'nT=bS, 8-hydroxydeoxyguanosine _Ej:'21t:Lt2b,J3 flo 3: f=,}-9 1) A.>8=jb'81 a#Jr*##@0)

t*hpSi9h'/i,951*vTh5%4i8=nSTJ 5 hT=bS, DNA 4Ai%tj:1'B9eLtfb,J3 flo Lf=Z)SJ3

TffJr&&##nteuDbS PFOA 8= i a _DNA&igo)j=f= aLFIEq 7113j?u 1 _I _i _bS*p2StlF5_31f=.

*WgE8=

ct9 PFOS i PFOA 8j:#L%Bb8=4fBfnJL,Tb,tibS 6, %h%hhi*jSli#%r& ti&iii*Jr4it V' 5

kf2a.%JB%#+a

I _{i bSPB E,bit} tf-,f:o

i;Rt8=-3 b ,I , *i45BJA=B-a-C>*3&XbSd*Jij<JB3?jcJB3?B3ELf%5RB;JBSWR*4o)

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2&# i _7ba _Jt?Wf-E&j:

1 ) Rg E] : Effects _of _{perfluorooctane} _sulfonate (PFOS) of swimming behavior _and _membrane _potential _of paramec1'um Caudatum

% a _zB

E3tI/1.-i,T#-:i:-i:_{_i} *.%.35

2) Rg p

Kawamoto, K., Nishikawa, Y., Oami, K., Jin, Y., Sato, I., Saito, N. _and Tsuda, S.

The Journal _of Toxicological Sciences

3eff* : _{33(2):155-161,} ₂₀₀₈

Perfluorooctanoic _acid (PFOA) but sulfonate (Pros) showed DNA damage Paramec1'um _Cauda tub

% a _f8 _:Kawamoto, K., Oashi, T., Oami,

J*Wi# 33B

K., Liu, N., Sato, I. _andTsuda, S.

The Journal _of Toxicological Sciences

i.%.i.#1i*:35(6):835-841, 2010

not perfluorooctane in comet assay on

W., Jin, Y., Saito,

3) Rg p : ultrasonic-induced tonic _convulsion in rats _after _subchronic

exposure to perfluorooctane sulfonate (Pros)

%T a _f%

JB3?Wi ## _f%

Kawamoto, K., Sato, I., Tsuda, S., Yoshida, M., Yaegashi, K., Saito, N., Liu, W. _andJin, Y.

The Journal of Toxicological Sciences

*.i.i.#41*:36(1):201l impress

BE#5E JBSWi5%i

1 ) Rg EL Neurotoxicity _{of perfluorooctane} _sulfonate (PFOS) in rats and mice after single oral exposure

i a _f% : Sato, I., Kawamoto, K., Nishikawa, Y., Tsuda, S., Yoshida, M.,

Yaegashi, K., Saito, N., Liu, W. _andJin, Y.

*a55F#%& : The Journal _of Toxicological Sciences

*. %l. i.#11* :_{34(5)..569-574,} 2009

2 )Lf a _:Air _purifiers that diffuse _reactive _oxygen _species _potentially

cause DNA damage in _the lung

% i _3% _:Kawamoto, K., Sato, I., Yoshida, M. _andTsuda, S

*ai#%i% : The Journal _of Toxicological Sciences