Diapositive 1Sex differences in the Developmental Origins of Health and Disease (DOHaD).
International Congress of Gender Medecine – Junior meets Senior -
Berlin - Germany Sept 22nd – 23rd 2015
SF-DOHaD
CVC
≤ 5
.5
120 Women
CORONARY HEART DISEASE Standardised mortality ratios in 10141 men & 5585 women
Barker et al, The Lancet 1989
Developmental
Poor resources Neonatal, infant mortality ratios = survivors but higher risk!
David J. Barker 1938- 2013
£
David J. Barker 1938- 2013
Charles & Junien QSP 2012
development and plasticity of tissue epigenome
Development
1 – Conditionning (programming)
functional decline
allostatic load
Threshold disease
1 - Prevent
1000 Days
Shift the focus, and change in strategy to avoid, cope with ill conditionning
2 – allostatic load
The DOHaD Revolution
Multi- & trans-
generational responses
+ Environment
+ Environment
+ Environment
to the ancestor(s) or parent(s) :
sex, type and timing of exposure
303 subjects and their 1818 parents and grandparents from 1890, 1905 and 1920 cohorts
Cardiovascular diseases Type 2 Diabetes Longevity / Mortality
Well- or undernourished
Ancestral origins of sexual dimorphism
(Bygren et al 2001; Kaati et al 2002; Pembrey et al, 2005)
Överkalix Cohorts
(Pembrey et al 2010)
Mortality depends on the sex and window of exposure of the grandparent Grand sons
PGF
Poor
Good
Age
Epigenetic changes during in vivo reprogramming
Which sequences escape germline reprogamming of
DNA methylation? In a sex-specific
manner?
Main routes
to the next generation(s).
(Pembrey et al, 2014)
exposure-induced non-coding RNAs (ncRNAs)
The exposure can affect the somatic tissues, the reproductive system and the germline
Female line
F0 F1 F2
Evolution :
between reproduction/survival
expectancy!
Specific features of transmission by fathers
(Curley et al 2011)
care
Postnatal investment
Prenatal investment
Following exposure, certain phenotypic characteristics may be inherited solely from the
father, solely from the mother, or from both parents ± equally.
The effects of, and responses to, developmental conditioning may affect offspring of both
sexes, or may affect one of the sexes more than the other.
Depending on the nature of the environment, the developmental window and duration of
exposure, the sex of the transmitting parent may also condition the type of response of
the offspring to the environment.
Different epigenetic mechanisms of environmental adaptation in males and females, in
both humans and model animals
The Barker hypothesis
U-shape curve
develop CVD in adulthood
Malnutrition, wars, stress, socieconomic status, education etc...
Les marques épigénétiques qui régulent la transcription génique
Heard et al., 2012
B. Stojkovic, Q. Wu, J.D Gothié, A. Gabory, A. Beauger, L. Attig, C. Junien, L. Sevin, D. Rousseau, L. Ferry, B.Karakas C. Gallou-Kabani, A.Vigé, MS Gross ...
IT-DIAB Consortium 2009-2014
IT-DIAB OSEO Coord Genfit (Lille)
C. Junien, L Attig, Q. Wu (Paris) B. Staels, P Lefebre (Lille)
D. Vieau (Villeneuve d’Asq) P. Fröguel (Lille/Londres)
H. Vidal (Inserm, Lyon) F. Pattou (Lille)
B. Cariou (Nantes) Spi-bio(Montigny le B.)
Roowin (Romainville) Genoway (Lyon)
Placenta network 2006-2010 ANR, FCA Coord C. Junien (Paris) C. Levy-Marchal (Paris) MA. Charles (Villejuif) I. Fajardy, A. Vambergue (Lille) J. Lesage, D. Vieau (Villeneuve d’Asq) C. Remacle, B. Reusens (Louvain) O. Picone, R. Frydman (Paris) A. Benachi, Y. Dumez (Paris) D. Vaiman (Paris) J. Tost (Evry) JP Jais (Paris)
CH3 CH3CH3
Acknowledgements
The phenotyping of descendants in animal models generally focuses on deleterious effects, ignoring the non-negligible proportion of “resistant” subjects with positive adaptive responses to the exposure of their parents or grandparents
Resilence/vulnerability = genetic background + 2 events : conditioning & responses
Responses opposite to the initial effects may also be observed. Overkalix cohort (Sweden) : male malnutrition before adolescence -> lower risk of CV death two generations later.
Responses observed in descendants may therefore be diverse and may differ from the initial impact on the parent, with anything from the vicious circle, most frequently reported, to an adaptation opening up unanticipated possibilities.
Gaps in phenotype description
Phenotypic explorations limited of the same system disturbed by parental or ancestral exposure
Interactions between the father and mother and between the young and their mother (microbiota) are relevant.
Mysterious intermediaries
On a sex specific mode
according to the sex of
SD in Inter or transgenerational transmission of the memory of exposure
(Gabory et al BSD 2013)
From conception.... until adulthood
40% Genes differentially expressed
effects”
X and Y chromosomes genes 1.5% Autosomal genes: expression 40%
- AFTER Birth
womanman gender
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