Programming effects of endocrine disrupting compounds in mice

Transcription

1 Programming effects of endocrine disrupting compounds in mice Joantine van Esterik 19 June Perinatal bisphenol A in mice 18 January 2011

2 Developmental Origins of Health and Disease (DOHaD) Adverse fetal environment leads to a functional change resulting in increased susceptibility to disease later in life Prenatal risk factors for obesity Over/under nutrition Disease Stress Smoking Exposure to EDCs?! tributyltin, diethylstilbestrol Dutch Hunger Winter

3 OBesogenic Endocrine disrupting chemicals: LInking prenatal exposure to the development of obesity later in life European Commission FP7 funded research project Project duration: May 2009 November 2013

4 Overview of project WP 1 Epidemiological data (human) Association EDCs and obesity WP 2 Experimental data (in vivo and in vitro) Underlying mechanisms WP 3 Risk assessment 7 partners (NL, B, SK, NO, F)

5 Hypothesis Perinatal exposure to EDCs may play a role in the development of obesity later in life Mechanism: altered epigenetics? Change in fat cell differentiation? EDCs? Change in early growth? Early exposure Changes in hormone and lipid metabolism? Adult phenotype

6 Hypothesis Perinatal exposure to EDCs may play a role in the development of obesity later in life Mechanism: altered epigenetics? EDCs? During development: EDCs EDCs? epigenetic make-up gene expression, cell functions lifelong change: altered programming

7 Study design Age ±17/42 wks: Challenge with high fat diet Maternal exposure Offspring not exposed -6w -4w -3w 0w 3w 23-28/53-57w Pre-mating Mating Gestation Lactation Juvenile/adult mouse hybrid C57BL/6J x FVB Dose range: subtoxic levels body weight fat pad weight histopathology food consumption physical activity serum lipid and endocrine profile glucose homeostasis epigenetic profile of liver DNA 2 non-invasive neurobehavioural tests immunotest (ex-vivo) internal dose

8 Overview results BPA PFOA TCDD PCB153 Overview results M F M F M F M F body weight / / growth sensitivity to high fat diet nd length food consumption nd nd - nd activity ucp1 expression organ weights - - / fat pad weights adipocyte size (WAT) na lipid accumulation (BAT) - - na serum lipid profile, glucose serum endocrine profile glucose homeostasis neurobehavioral function na na immune function na na -

9 BPA serum free fatty acids Males Females

10 Overview results BPA PFOA TCDD PCB153 Overview results M F M F M F M F body weight / / growth sensitivity to high fat diet nd length food consumption nd nd - nd activity ucp1 expression organ weights - - / fat pad weights adipocyte size (WAT) na lipid accumulation (BAT) - - na serum lipid profile, glucose serum endocrine profile glucose homeostasis neurobehavioral function na na immune function na na -

11 PFOA females fat pad weight growth (bw wk 27/ bw wk5)

12 Overview results BPA PFOA TCDD PCB153 Overview results M F M F M F M F body weight / / growth sensitivity to high fat diet nd length food consumption nd nd - nd activity ucp1 expression organ weights - - / fat pad weights adipocyte size (WAT) na lipid accumulation (BAT) - - na serum lipid profile, glucose serum endocrine profile glucose homeostasis neurobehavioral function na na immune function na na -

13 Splenic lymphoproliferative responses TCDD MALES FEMALES dose-response spleen weight IL-4 IL-4 (pg/ml) * males females mitogen: cona IFN-γ (pg/ml) control 4 TCDD TCDD IFN-γ * 1 0 males females mitogen: LPS control TCDD TCDD pg pg

14 Overview results BPA PFOA TCDD PCB153 Overview results M F M F M F M F body weight / / growth sensitivity to high fat diet nd length food consumption nd nd - nd activity ucp1 expression organ weights - - / fat pad weights adipocyte size (WAT) na lipid accumulation (BAT) - - na serum lipid profile, glucose serum endocrine profile glucose homeostasis neurobehavioral function na na immune function na na -

15 Summary EDCs analyzed in our model can induce programming BPA, PFOA, TCDD, (PCB153 marginally) can alter the metabolic phenotype can have immunological effects act compound- and sex-specific are conditionally * obesogenic * experimental conditions, e.g. species, sex, housing, diet, microbiome

16 Discussion literature is inconsistent different background conditions, e.g. species, strain, dose, exposure route/window, diet but also statistics > 20 BPA low dose studies with early exposure window MALES FEMALES BW BW - BW BW BW - BW BW effect - 9 studies sexes equal - 3 studies sex-specific

17 Discussion literature is inconsistent different background conditions, e.g. species, strain, dose, exposure route/window, diet but also statistics epigenetics (e.g. DNA methylation) can be the mechanism behind programming however, our BPA study did not show DNA methylation changes in liver of female offspring some effects occur at low concentrations adverse? implications for risk assessment

18 Conclusion perinatal exposure to our analyzed EDCs can program for an altered metabolic phenotype later in life and is conditionally obesogenic other areas such as immunology can also be affected by programming sex specificity of effects supports interaction of the toxicants with endocrine functions determining the normal program

19 Acknowledgements RIVM Netherlands Leo van der Ven Martijn Dollé Hennie Hodemaekers Jeroen Pennings Sandra Imholz Joke Robinson Eugène Jansen Piet Beekhof Bhawani Nagarajah Marianne Roodbergen Eric Gremmer Henny Verharen Wout Slob Ilse Tonk NVI Netherlands - Animal caretakers VU University Amsterdam Netherlands - Juliette Legler - Liana Bastos Sales - Timo Hamers - Peter Cenijn - Jorke Kamstra - Stefan van Leeuwen - Jacco Koekkoek - Marja Lamoree Scientific Advisory Board - Rebecca Simmons, Penn Medicine European Commission