Toxicological Research on Environmental Endocrine Disruptors

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1 21 2Π PROGRESS IN CHEMISTRY Vol. 21 No. 2Π3 Mar., ( ), 2 2,, ; 2 2,,, : X17115 ; X826 ; R335 : A : X(2009) 02Π Toxicological Research on Environmental Endocrine Disruptors Shi Xiongjie Liu Chunsheng Yu Ke Deng Jun Yu Liqin Zhou Bingsheng 3 3 ( Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan , China) organs. Abstract Most evidence in terms of endocrine dsiruptors ( EDs) mainly originates from studies on reproductive However, in veterbrates, the ability to attain reproductive and development success relays on the intact organization of a complex endocrine system. Disturbances in the regulation of the key hormones and receptors functioning along this system may cause detrimental effects on reproduction and development. Here we reviewed recent studies of EDs on endocrine system. EDs may act on key hormones and receptors along with the hypothalamic2pituitary2gonald ( HPG) axis and lead to reproductive failure. Thyroid disruption may be caused at different levels, for example, the synthesis, transport, binding and cellular uptake along with the hypothalamic2pituitary2thyroid ( HPT) axis. Knowledge of model of action EDs is largely via receptors2mediated pathway and alternatively may affect on steroid hormone synthesis. Aquatic hypoxia can influence fish reproduction and thus it is also an endocrine disruptor. Molecular techniques, such as toxico2 mics, transgenic fish will be employed as powerful tools for environmental EDs risk assessment, as well as in elucidating mechanisms of model action. Key words endocrine disruptors ; endocrine system ; risk assessment ; toxicology Contents 1 Hypothalamic2pituitary2gonadalΠthyroidΠadrenal axis 111 Hypothalamic2pituitary2gonadal axis (HPG axis) 112 Hypothalamic2pituitary2thyroid axis(hpt axis) 113 Hypothalamic2pituitary2adrenal axis (HPA axis) and in vitro model 2 The effects of aquatic hypoxia on endocrine system in : (No ) 3 3 e2mail ac. cn

2 2Π3 341 fish 3 The application of omics in endocrine disruptor research 4 The application of transgenic fish in endocrine disruptor research 5 Perspectives of endocrine disruptor research (endocrine disruptors, EDs),, ( POPs) ( ),,,,,,,,,, 2 [1 ],,,, 2 2 Π Π,,,,, [2 5 ] (,, ),,,,, [4 ],,,,,,,, 2 2 Π Π,,,,, (cross2talk),,, [1 10 ],,,, Π Π (HPG axis), 2 2 (HPG) ( 1) ( GnRH), GnRH (FSH) (LH),FSH LH, (FSHR) (LHR),

3 [11 14 ] FSH (CYP11A) (20 2HSD), LH 20 2HSD 17,20 2 (17, 20 2dihydroxy242pregnen232one) [15 ], (activin) (inhibin),,,, A ( HMGR) ; ( StAR) ; 2 ( 3 2HSD 20 2 HSD) ; (CYP11A) ; P450 ( P450c17, P450c19, P450c21) (CYP11B),, ( testosterone, T), (estradiol, E2) 112 ( 112ketotestosterone, [11 112KT) 14 ],T E2 [16 ], activin inhibin T E2 112KT [15 ],, ( ER) (VTG), hypothalamus: ; pituitary : ; testes : ; ovary: ; liver : ; GnRH : ; FSH : ;LH : ; steroid : ; T: ; E2 : ; 17, 20 2DHP : 17, 20 2 ; vitellogenin : ;CYP11A : ;3 2 HSD : 2 ; CYP19A ; CYP17 : 17 2 ; Fig. 1 The HPG axis in fish, showing the regulatory and feedback pathway [15 ] ER, HPG, ER,,,,, CYP19A CYP19B,,,, [18 ], Zhang prochloraz ketoconazole (medaka) HPG, 6 [14 ] [17 ], Zhang ( 17 2, 2 2 (HPG),, Villeneuve fadrozole (fathead minnow) HPG,, ethinylestradiol, EE2), (17 2trenbolone, TRB) fadrozole HPG [12 ], PCR, HPG,,

4 2Π3 343 (zebrafish), (6 :2FTOH) HPG,, 2 2,,,, HPG PCR,, ( regulatory test) (HPT axis) [19 ] HPG, HPT ( 2), HPT (TRH), ( TSH), TSH TSH, [19 ],TSH (corticotropin2releasing hormone, CRH), CRH TSH (ACTH) [20 ], HPT (thyroglobulin,tg) Tg, Π ( sodiumπiodide symporter,nis) [19 ], NIS, (transthyretin, TTR), (deiodinase), T4 (thyroxine) T3 (triiodothyronine),,, T3 T4 TSH CRH [19 ] HPT HPT PCR HPT Π hypothalamus : ; pituitary : ; centre nerv : ;thyroid : ;adrenals : ;CRH : ; TSH : ;ACTH : ;T2 : ;T3 : ;T4 : ; rt3 : ;TTR : ;DI: ; RXR : ;TR : Fig. 2 HPT and HPA axis in fish, showing the regulatory and feedback pathway,,, ( PCBs) (PBDEs) HPT, [19 ] Brown PCB126,, T4 T4,, T3 T3 [21 ] LeRoy PCB (A1254)

5 PCB153, PCB 47 PCB77 T3 T4, T3 T4, [22 ],,, Kuiber (DE271), T3 T4, T3 T4, DE271 [23 ],Shi,PFOS, (hhex pax8), [24 ], DE271 HPT, DE271 HPT HPT DE ( HPA axis), 2 2 (HPA) [25 ] (CRH), CRH (ACTH), ;, [25 ], Li HPA,,, (cortisol), (ACTH), (CRF), [26 ], HPA,, HPA,,, DDT, PCBs [27 ], ( H295R),, 3 (H295R), PCR,, Cyp19,,,PCBs [28 37 ] H295R :,, ( ) 10, PCB2126 H295R (cortisol) (aldosterone), [38 ], Li,,,, (reproductive neuroendocrine toxicity)

6 2Π H295R [37 ] StAR : ;HMGR : A ;CYP11A : ;3 2HSD : 3 2 ;CYP21 : 212 ;CYP11B2 : ;CYP17 : 172 Π17, 202 ; CYP11B1 : 11 2 ; 17 2 HSD : 17 2 ; CYP19 : ; cholesterol : ;pregnenolone : ;progesterone : ; 112 deoxycorticosterone: 112 ; corticosterone : ;aldosterone : ;17 2OH2pregnenolone : ; 17 2OH2progesterone : ; 112 deoxycortisol : 112 ; cortisol : ;DHEA : ; androstenedione : ;testosterone : ; 17 2estradiol : 17 2 ; zona glomerulosa : ; zona fasciculate : ;zona reticularis : Fig. 3 Schematic representation of the steps involved in steroid hormone synthesis pathways in H295R cells [37 ],, DNA,,, [39 ] 2,,,,,,,, 20 % (estradiol and testosterone), 92 %, 4 % [40 ] Thomas ( atlantic croaker), (VTG) Florida, [41 ],Shang [42,43 ], F1, 7414 %, 6119 %,, 3 2HSD CYP11A CYP19A CYP19B, Π, ( ), P450,, (hypoxia2inducible factor21, HIF21), HIF21,,,

7 346 21, 3, (2omics), (gene chip),,,,, (expression signature),,, ( biomarkers), Moens cdna, 14, 14 : A 112, [44 ] Wang MCF27, IGFBP4 HSPA8 B4GALT1 XBP1 KRT8 GTPBP4 HNRPAB SLC2A1 CALM1,ID2 ZNF217 3, [45 ] Naciff 3 ( A), , 3, [46 ] Benninghoff Williams DNA ( E2) ( TAM) ( E2 + TAM) (DES) (DHEA) (cortisol),e2 49, E2 DES DHEA 18, 18 DHEA TAM E2 ; TAM VTG1 [47 ],, IEF ( )ΠSDS2PAGE (2DE) [48 ],, (MALDI2TOF2MS) (SELDI2TOF2MS)

8 2Π3 347,,,, Walker SELDI2TOF2MS (sheepshead minnow) ( E2) (MXC) A (BPA) (TPP) ( ES) (CP), SELDI,E2 42, 30 E2, E kDa, 13 3, MXC BPA TPP E2, ES CP [49 ] (variegatus zona radiata) [50 ] (metabonomics) Π,, [51 ],, Samuelsson 1 H NMR [52 ] 4 [53 55 ],, [56 ] VTG, GFP, GFP, F1 [57 ],, GFP,,, [58,59 ], Zeng mvtg1 : gfp, ( GFP) 21 (VTG21) ( E2),,,GFP EE2, (DES), (estriol, E3) A [60 ] Kurauchi [61 ] 5 ChgH2GFP ChgH2GFP choriogeninh(chgh) ( GFP) GFP pM ( E2) nM 5, 7, 452 ( ) nM,,18315pM ( E2) GFP, GFP [62 ] Ueno chg2l115 kbπgfp emgbπrfp 1 2, (RFP), chg2l115 kbπgfp2emgbπrfp E2 GFP [63 ], (RFP) ( GFP),,

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