Developing AOPs from PPAR Activation Leading to Reproductive Toxicity

17 Pages·2014·0.62 MB·English

Peroxisome proliferator-activated receptors (PPARs)
activation leading to reproductive toxicity in rodents
Małgorzata Nepelska
www.jrc.ec.europa.eu
Adverse Outcome Pathways:
From Research to Regulation
September 3-5, 2014
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At the beginning
 We had an AIM

To develop a strategy for building a MoA based chemical category
chemical structure
f( ) = toxicity
f(MoA)=

How?
2
Building MoA-based chemical category for toxicity prediction

STEP 1. Chose endocrine active, data rich chemicals

STEP 2. MoA matrix display of experimental data
MIE KE
AO

Phthalates ER PPAR AR AhR Sertoli spermato Leydig Decreased stereodo oestrus reprModaulect ive Sperm Decreased
cells genesis cells testosterone genesis cycle parameters AGD
tract

DEP 0 1 1 1 0 0 / 0
DiBP 1 1 1 1 1 1 1 1 1
DPP 0 1 1 1 1 1 1 1
DCHP 0 0 1 1 1 1 1 1 1 1 1
DHP 0 / 1 1 1 1 1 1 1 1
DINP 0 0 0 1 1 1 1 1 0 1 /
DIDP 0 0 1 0 0 / 1 0
DnOP 0 1 0 0 /
BBP 1 1 1 1 1 1 1 1 1 1 1
DprP 1 1 1
MEHP 1 1 1 1 1 1 1 1 1 1

DEHP / 1 / 1 1 1 1 1 1 1 1 1
STEP 3. Mechanistic "blueprint" of phthalates

STEP 4. Search for mechanistic analogues (other chemicals that
have similar MoA)
3
PPAR activation leading to reproductive toxicity in rodents

MIE KE Adverse Outcome

AOP-linked

chemical
initiators
PPAR  cholesterol  Hormone  H ormone Reproductive
activation transport synthesis levels toxicity

4
MIE
PPARs peroxisome proliferator-activated receptors
Nutrients
Fatty acids Xenobiotics
 family comprises the types α, γ and β/δ Growth factors
Endocrine disruptors
 are nuclear receptor superfamily of
transcription factors that respond to specific
ligands
 regulate lipid and carbohydrate metabolism
PPARα,γ β/δ
 embryonic and foetal development regulated genes
 cholesterol uptake and transport embryonic and foetal
vascular functions development
 represent a potential molecular link between
intracellular trafficking of lipids
reproductive function and carbohydrate and
Lipids and carbohydrates metabolism
lipid metabolism
inflammatory responses

5
MMIIEE
PPAR activation: evidence
Chemical In vitro in vitro Knock-out/inhibition/increased
initiator binding transactivation expression
Experiments with PPARα-null mice
DEHP - + indicate involvement of the receptor
in reproductive toxicity of phthalates
Inhibition studies
MEHP + +

+
BBP +/- To be verified

+
DBP +/-
To be verified
+ Increased expression PPARγ
Bisphenol A
-
Increased expression
Butylparaben - +
PPARγ
6
KE
Altered steroidogenic pathway
3 β -HSD-III
pregnenolone progesterone
P450scc
cholesterol
Chemical StAR androstenedione
cholesterol
initiator
TSPO aromatase
17β-HSD IV
estrone
PPAR
testosterone
binding&activation
estradiol
aromatase
KKEE AO
Chemical Decreased Malformation of
Testicular toxicity
Initiator testosterone levels reproductive organs
+ + +
(Howdeshell et al., (Gray et al., 2000)
DEHP (Kwack et al., 2009)
2008) (Parks, 2000)
+ + +
(Howdeshell et al., (Gray et al., 2000)
BBP (Gray et al., 2000)
2008) (Nagao et al., 2000)

+ + +
(Howdeshell et al., (Barlow et al., 2003)
(Mylchreest, 2000)
DBP 2008) (Mylchreest, 2000)

(Barlow et al., 2003)
(Mylchreest, 2000)
+ +/- +
(Tanaka et al., 2006) (Takagi et al., 2004)
(Talsness et al., 2000)
(Nakamura et al., (Kobayashi et al., 2002)
Bisphenol A
2010) (Talsness et al., 2000)
(Talsness et al., 2000) (Tinwell et al. 2002)

+ + +
Butyl
(Zhang et al., 2014) (Zhang et al., 2014)
paraben (Oishi et al., 2001)
+ effect present
/ no change
? no information 8
*testosterone production
PPAR activation leading to reproductive toxicity in rodents
MIE KE Adverse Outcome
cholesterol
PPAR t ransport to  Hormone  H ormone Reproductive
activation synthesis levels toxicity
mitochondria
Altered oestrus cycle Malformation of

Decreased ovary weight reproductive organs

Decreased AGD
Hypospadias
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PPAR activation leading to reproductive toxicity in rodents
cholesterol
PPAR  Estradiol Hormone Reproductive
transport to  
activation synthesis levels toxicity
mitochondria
p
cholesterol r
AOP 1 PPAR t ransport to t e stosterone  Hormone Reproductive en
activation synthesis levels malformations t
mitochondria a
l

cholesterol
AOP 2
PPAR t ransport to  Estradiol  Hormone Altered
activation synthesis levels estrus cycle
mitochondria
a

d
u

l
t
cholesterol
AOP 3 PPAR t ransport to t e stosterone  Hormone Testicular
activation synthesis levels toxicity
mitochondria
10