Chemical pollutants of the food chain. Catherine Viguié CR INRA.

Chemical pollutants of the food chain.

Catherine Viguié CR INRA

Type of contaminations

ENVIRONNEMENT (water/soil/air)

Végétal Animal

Human

Pollutants evolution in the environnement Different pathways for molecule chemical

transformations Abiotic (oxidation – light-unduced) Biotic (through alive organism from bacterias

to and vegetal organisms) Consequences:

From one initial molecule to numerous metabolites

Inactivation (liver metabolism) Bioactivation (metaboliste more toxic than

the first molecule)

Modulation of toxicity (1)

Transport mechanisms through the Physiological barriers

Passive diffusion Active transporters (specifics) Efflux pumps Physical barriers (tight junctions)

ABSORPTION

(Digestive tract)

Determining step for blood concentrations:

global exposure

Exposure of target tissues

Brain

Placenta-Foetus

Potential for toxicity

Competition for transporters

Plasma transportation

In the blood the molecule can be free or bound

Binding can occur with specific or non specific transporters

Limiting factor for clearance mechanisms

highly bound molecules to specific transporters (binding proteins) :

high potential for bioaccumulation

Potential Toxicity

Competition with specific binding protein of endogenous molecule such as hormones will be associated to an increase in hormone clearance


METABOLISMPhase I (cyt P450): enzymesPhase IIElimination (kidney – liver)

BIOACTIVATION vs. DETOXIFICATION

Limiting factor for the elimination of the

xenobiotic

•Bioaccumulation

Potential toxicity•Competition/inhibition of enzymes•Induction of enzymes


Mechanisms and sites of action

Endocrine disruptors Metabolism of hormones Transportation Receptors Hormone synthesis

Pathogens (bacterias- parasites) Resistance to therapeutic agents

Central nervous systems Neurodegenerative diseases Alteration of the development of the central nervous system

Cancers

Effects are dose and time dependent

Oral contamination very low doses

+ Long period exposure

Mecanisms of actionCritical period

The relevance of animal model for the risk analysis of food contaminant for human health

Transport mechanisms through the Physiological barriers

placenta

efflux pumps Metabolism of the toxic Physiology of the

altered function: Plasma binding Neuroregulation Hormone metabolism

=

All these phenomenon = causes for interspecies differences in the sensitivity to toxic effects of xenobiotics =>Need for relevant model for human from the standpoints of:

the metabolism of the xenobiotic the regulatory scheme of the function

The thyroid function

HypothalamusTRH

ThyroïdTPOTGNIS

Pituitary TSH

bound TH (T3 T4)

blood

Clearance

-

free T3, T4

HOT spot 1

HOT spot 2

Whole body / all life effects

HOT spot 3

Hot spots: debates on the relevance of animal models

80% o

f circ

ulatin

g T3

The relevance of animal model: analysis of the case of the evaluation of fipronil as a thyroid disruptor

TRH

TSHThyroid

Hypothalamus

Anterior pituitary

T3, T4 freeT3, T4 bound PL

Clearance

-

Fipronil

Increased T4 clearance// hepatic enzyme induction

Fipronil and thyroid disruption in the rat

0

0.2

0.4

0.6

0.8

Solvant Fipronil

(mL/m

in/k

g) *


T3, T4 freeT3, T4 bound PL Clearance

Fipronil

With is the pathophysiological scheme of action of fipronil as a thyroid disruptor considered as non relevant to human?

TBG expression: •protects TH from peripheral elimination•Pool of TH

Bound T4:TBG 73% 53% 0% in adultTTR 19% 36% 85%Albumine 8% 11% 15%

To be

OR

?

Not to be

The question is :What is the relevance of animal models for an endocrine system that exhibits multiple interspecies particularities in its regulatory scheme ?

The sheep as a good model to study thyroid disruptors?


The protective role of specific thyroid hormone binding protein TBG

•Free T4 fraction (%) 0.02 0.04 0.07•T4 half-life (Days) 2 5-9 0.5•TBG

T4 Dissociation constant (nM) 0.112 0.105 NA/adultT4 Maximal binding capacity(nm/l) 160 266

•TTRT4 Dissociation constant (nM) 7.14 6.25 2.78T4 Maximal binding capacity(nm/l) 4494 3230 3968


Does the effect of fipronil on thyroid function differ between rat en sheep accordingly to the assumes protective role of TBG?

0

0.2

0.4

0.6

0.8

Vehicle Fipronil

(mL/m

in/k

g)

0

20

40

60

80

0 10 20 30

Tota

l T4 (

ng

/ml)

Vehicle

Fipronil

0

80

160

240

0 25 50 75 100 125

Temps (h)

Tota

l T4

(ng

/ml)

0.00

0.01

0.02

0.03

0.04

before after

(mL/m

in/k

g)

*

THX+ T3

YES


Is the interspecies difference in TBG expression the only explanation for the diffrential effect of fipronil on thyroid function between rat and sheep?

The role of fipronil metabolic pathways

10

100

1000

10000

0 5 10 15 20

Time (days)

Pla

sm

a c

on

cen

trati

on

s (

ng

/mL)

Fipronil administrations

Fipronil

Fipronil sulfone

10

100

1000

0 5 10 15 20 25 30 35Temps (j)

Sulfone

Fipronil


Is the interspecies difference in TBG expression the only explanation for the diffrential effect of fipronil on thyroid function between rat and sheep?

The role of fipronil metabolic pathways

Hypothesis: transformation of fipronil in fipronil sulfone (hapatic cytochromes) = bioactivation relative to potential thyroid toxicity. Sensitivity

to fipronil as a thyroid disruptor is modulated by hepatic metabolism of fipronil (‡ between species)

100

1000

10000

Fipronil Sulfone

Pla

sm

a c

on

cen

trati

on

(n

g/m

l)

100

1000

10000

Fipronil Sulfone

Pla

sm

a c

on

cen

trati

on

s

(ng

/ml)

Sulfone/FIP= 4Sulfone/FIP>100

Conclusion

Never forget the physiology (function & metabolism)

The relevance of experimental animal model should always be addressed carefully

Necessity to develop and adapt these models to allow long term low dose exposure studies relevant to human exposure

The need for physiologically-based models allowing a global assessment of endocrine function with a predictive value and mechanistical outlets.

Chemical pollutants of the food chain. Catherine Viguié CR INRA.

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