XY XX

XX / XY

1990

SRY

DMRT1 DM-W/

XX / XY

XX XY

Hd-rR

cDNA 1356 267 5594

Dmy (DM-domain gene on the Y chromosome)

doublesex mab-3 DNA

SRY

DM-

DM-

- 2002 -

1 2 4 5 63

XX

XX + Dmy

Gain-of-function

RNAi

XY

XY Dmy

Dmy

- -

Loss-of-function

XY - Dmy (RNAi)

( )

XY

XY

XYDmy

Amh

Dmrt1Sox9a2

KT

Foxl2 Cyp19a1

E2

Ad4BP/SF1

XX

Rspo1

E2

10

XY XX

Gsdf

Gonadal Soma Derived Factor

0

100000

200000

300000

400000

500000

600000

700000

800000

gsdf

gsdf

XY XX

A B

Dmy Gsdf

Gsdf

0

20

40

60

80

100

120

400

0

800

1200

1600

Dmy

4 5 6 7 8 9

XX

XY

DAPI

Gsdf

Merged

Dmy Gsdf

10 �m

Dmy

20

XY XX XYGSDF

DMY

GSDF

GSDF

XYDMY

KT

XX

E2

AMH

DMRT1Sox9a2

E2

GSDFAd4BP/SF-1

Cyp19a1Foxl2

Rspon1

ER�2

XYDMY

KT

XX

E2

AMH

DMRT1Sox9a2

E2

Ad4BP/SF-1

Cyp19a1Foxl2

Rspon1

ER�2

Gsdf

Rela

tive e

xp

ressio

n t

o E

f1�

7 86 7 86 7 86

� E2

ER� ER�1 ER�2

XX XY

ER�2

ER� ER�1 ER�2

ERs

E2

ER�2

XX

E2

ER�2

XX

Exposure to Diethylstilbestrol During Embryonic and Larval Stages

Medaka Fish (Oryzias latipes) Leads to

Sex Reversal in Genetic Males and Reduced Gonad Weight

In Genetic Females

Bindhu Paul-Prasanth, Yasushi Shibata, Ryo Horiguchi, and Yoshitaka Nagahama

Endocrinology (in press)

SE

8 8-18 8-128

LE

18

28

18-28 18-128

LE

DES

DES

DES

0 6 8 18 12828

XY

XX

Cyp19a1

DMY

DES

Short exposure

Long exposure

0

400

600

XY XX

200

DES (ng/ml)

800

Co

nt

0.0

1

0.1

0

1.0

0

10

.00

10

0.0

0

Co

nt

0.0

1

0.1

0

1.0

0

10

.00

10

0.0

0

DES

0

200

300

XY XX

100

DES (ng/ml)

400

Co

nt

0.0

1

0.1

0

1.0

0

10

.00

10

0.0

0

Co

nt

0.0

1

0.1

0

1.0

0

10

.00

10

0.0

0

1 ng/ml

DES

Bipotential gonad

XY XX DESXY

8 dpf

18 dpf

Ge

rm c

ell

nu

mb

er

0

400

800

8 18 8 18

XY XX

Brd

U-p

osit

ive g

erm

cell n

um

ber

0

80

120

XY XX

40

8 18 8 18

XX 18 days after fertilization

Positive control Control DES

Effects of DES on germ cell apoptosis (TUNEL technology)

80 �m

XY XX

Effect�of�DES�on�gonado�somatic�index�(GSI)

Cont

XY

SE-

Washed

XY

LE-

Washed

XY

Cont

XX

SE-

Washed

XX

LE-

Washed

XX

0.00

2.00

4.00

6.00

Gon

ado-

som

atic

inde

x (G

SI)

SE

8

SE

8

DES

DES

DES

XY

8 dpf 8 dpf Scp3

Gsdf

18 dpf 18 dpf

Gsdf

Scp3

LE

18-28 28-128

DESDES

XY

LE

18-28

DES

Gsdf28 dpf 28 dpf 42sp43

Gsdf28 dpf 28 dpf 42sp43

8000

6000

4000

2000

0

Effect�of�DES on�Dmy�expression

Cont LE Cont LE

XY XX

18-28 18-28

Effect�of�DES on�Gsdf expression

XY XX

Cont LE Cont LE

20000

0

40000

60000

80000

Gsdf XX

Effect�of�DES on�Dmrt1 expression

XY XX6000

4000

2000

0

Cont LE Cont LE

0

2000

4000

6000

Effect�of�DES on�Cyp19a1 expression

Cont LE Cont LE

XY XX

DES Cyp19a1

DES

XY XX

Cyp19a1 expression�after�withdrawal�of�DES

20000

16000

12000

8000

4000

0

Cont SE LE Cont SE LE

DES Cyp19a1

DES

DES

DES

Gsdf

50%

DES GSI

DES

Cyp19a1

DES

DES

Foxl2/Cyp19a1

E2/ER�2

XY XY

DES

Dmy

Gsdf

Dmrt1

Foxl2/Cyp19a1

E2/ER�2

Dmy

Gsdf

Dmrt11