y y y Nutritional Intervention Preconception and ption l l l n n n During Pregnancy to Maintain Healthy Glucose thy Gl Gl Glu Gl O O O Metabolism & OffspRing Health Health th e s U l a n o Keith Godfrey , with Chan Shiao-Yng, Wayne Cutfield, Chong Yap Seng Yng, Way ayn s r Director, NIHR Southampton Biomedical Research Centre in Nutrition Biomedica cal e Professor of Epidemiology & Human Development, MRC Lifecourse Epidemiology ogy & Hum man P Unit & University of Southampton Southampto ton r Visiting Professor, National University of Singapore Na ona l U o Honorary Consultant, University Hospital Southampton NHS Foundation Trust onsultant, U Uni F Twitter @KeithMGodfrey KeithMGo God
y y y A healthy start to life has lasting benefits for nefits l l l n n n multiple organs & control systems in the offspring in the off off ff ff O O O e • Fat, muscle & bone s • Heart, lungs & kidneys U • Metabolic & stress responses l • Mood & behaviour a • Ability to learn & cognitive function n • Timing of puberty, reproductive function functio on o • Immune responses s r e P The effects can be subtle, but they have lifelong consequences, n be sub ubtl r r altering how a person responds to their later environment & a p ers so o o lifestyle F F
y y y y y Men ( ) & women ( ) born after a famine period ( ) contribute ) l l l an excess of diabetic patients - total population of Austria on of A Au u n O n n o o F Thurner et al PNAS 2013
y y Developmental influences ces l l n n O O Uterine environment Postnatal environment e e.g. gestational e.g. mode of delivery y s diabetes, mother’s early nutrition diet, mother’s stress U Genotype l l a n o s r e P Phenotype Phenotype Phenotype e.g. e.g. e.g. r Health Birth weight Adiposity o o Disease Gestational age Growth F F Body composition Neurodevelopment Epigenetic Modification
y y l l n n Nature, 6 th November 2008 8 O O e s U “When “When scientists opened up the en l human genome, they expected to find hum ma a the genetic components of common the n traits and diseases. But they were nowhere to be seen. o s Brendan Maher shines a light on six places where the missing loot could be r stashed away.” e P r o F
How is the “memory” of early life experience held - epigenetics ep y y y l l l n n n The development & maintenance of plants & animals is orchestrated by hestrated ed ed ed O O O reactions that switch parts of their DNA on & off at strategic times & locations. ategic times es & & Epigenetics is the study of these reactions & the factors that influence them.* rs that in influ e e Plants & animals use epigenetic processes to adapt their development to the pt th de d s environment experienced in early life U Feeding bee larvae royal jelly for 6 days (vs (vs l l l the usual 3 days) alters growth & development elop ment nt a a a n n n o o o o s s Queen r r Epige Epigenetic processes ene e e e e (DNA (DNA methylation, HDACi, miRNA) me P P P P r o Larva va F Worker *Adapted from http://learn.genetics.utah.edu/content/epigenetics/ en
y y y Epigenetics & the human genome nome e e l l l n n n O O O O O O Human genome: 3.2 billion CGAT bases, 200 GB data, 30 million CpG sites ata, 30 0 e s � 3% protein coding (23,000 genes, ~half expressed in each cell) express sed d U � 77% proposed to have functional elements (ENCODE) ements (E EN l a a Human body - 50 trillion cells: different but same DNA (2 metres /cell) nt but sa n n o s Epigenetics underlies differences between cells ences be betw r e � Changes in gene function that do not depend on DNA sequence ction that at P P � Gene expression changed: methylation of CpG sites & chemical n changed ed: changes in the histone proteins alter “ packaging ” of DNA; non-coding h ston e p r r o RNAs have a variety of roles that alter gene transcription a vari ty o F
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Epigenetic “marks” in perinatal tissue : strong associations so y y y y y y with childhood fat mass & % fat in 2 independent cohorts dent c o o l l l l n n n O O O O Southampton Women’s Survey thampton W Wo Princess Anne Hospital study children aged 9 years children aged 6 years childre en a e e e 25.0 28.0 8.0 s U 26.0 26 l a 20.0 n n n o o o 24.0 s s s s s r r r 15.0 e e e e e 22.0 P P P r r r r r o o 20.0 10.0 -40% -60% -80% >80% -40% 40% - -60% 60 -80% >80% F Umbilical cord RXRA Um mbi Umbilical cord RXRA SH amp1 CpG13 methylation SH am SH amp1 CpG13 methylation Godfrey, et al. Diabetes 2011 Values are means + SEM m
y y y y y y l l l l n n n n Changing the mother or ging the m mo ot o O O O father’s nutrition er’s nutr itio before/during pregnancy e/dur rin e e can result in fat & lazy an re su ult s s “couc “couch potato” offspring … uch U U Courtesy of Liggins Institute
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Investment in human capital antenatally & preschool results y y y y in increased rates of return l l n O U l a n F Doyle, Heckman, et al. Economics & Human Biology 2009
Maternal supplementation with 1000 IU Vitamin D: m y y y MAVIDOS multicentre RCT in 965 pregnancies nancie l l l n n n O O O O O O O O O O Reduces maternal …. and increases offspring creases off ffs vitamin D insufficiency bone mass in winter births s in winte ter e e e e e e e e 34 weeks 34 weeks Winter births er birt ths Winter gestation gestation (D (Dec to Feb) F Fe s s s s s s s 70 70 70 100 100 U U U U 83.3 83.3 Percent women 25(OH)D> 50nmol/ l Percent women 25(OH)D> 50nmol/ l ntent (g) Neonatal bone mineral content (g) 80 80 l a co n n 60 60 o o 60 60 60 36.9 36.9 s 40 40 r r r e e e e e 20 20 P P P P P P P P P P r r r r r r r r r p= 0.003 0 0 p= 0.003 50 50 50 o o o o placebo 1000 iu/d Placebo Placebo 1000 IU/ day 1000 IU/ day Mean (95% CI) F F F p interaction treatment group x season = 0.03 34 34 k k Cooper et al. The Lancet Diabetes & Endocrinology 2016
y y y UPBEAT: UK Better Eating and Activity Trial ty Tria l l l n n n UPBEAT UPBEAT O O O Pregnancy low glycemic index diet reduced infant fatness uced inf nfa e age 6 months s U U U U U U U Beneficial effect of prenatal intervention dependent on prolonged breastfeeding: endent on on p l l l l l l l a a a a a a a a a a n n n n n n n n Reduction seen when 3 or more months o o o o o o o exclusive breastfeeding s s s s s s s s r r r r r r r r e e e e e e e P P P P P P P No reduction from prenatal intervention if less than 3 months exclusive breastfeeding -2 -1.5 -1 -0.5 0 0.5 1 * Triceps Skinfold Thickness (mm) Patel, Godfrey, Poston, et al, Int J Obesity 2017
y y y Public Health Canada – Preconception Health Recommendations ommen l l n O r o F
y y y Iodine status of 30 countries in the EUthyroid project yroid l l l n n n O O O r o F Background colour refers to the iodine status in the general population; line colour represents the iodine status of pregnant women. refers to the io iod Countries with solid colours have the same iodine status in both the general population and in pregnant women. olour have TLDE 2016
0.49 SD lower IQ age 7 years* in children whose mothers had mo y y y l l l preconception iodine deficiency (9% of 654 Southampton mothers) hampton n n n n O O O 0.4 e 0.2 Child’s WASI full IQ 0 age 7 years (z-score) -0.2 -0.4 -0.6 s r -0.8 8 e P -1.0 -1.0 ≥50 to ≥100 to ≥150 <50 <100 <150 r Mother’s preconception urinary o iodine:creatinine ratio μ g/g F *Adjusted for maternal IQ, maternal education and maternal pre-pregnancy BMI, breastfeeding duration, aternal IQ, ma mate smoking in pregnancy (yes/no), sex, age & maternal iodine intakes in pregnancy ancy es/n Robinson, Godfrey, et al. J Nutrition 2018
Singapore: ideal for studying ng y y y l l l n n n ethnic differences O O O • Genetic • Total Population e – 3 distinct ethnic groups ethnic ic g – 5 million (3.8 million citizens & – Intermarriage rate of about 18% ermarr ge e s permanent residents) • • Nutritional Nutritional Land Area U – – – Distin Distinct ethnic cuisines ct e 712 sq km – – • Sh Shared by all ethnic groups are Literacy Rate l • • Cultural Cultu ura – a 95.9% – • Distinct cultural practices Resident population living in n – Increasingly globalized government-subsidized housing ng o • – Environmental 82% • – s Very similar Home Ownership Rate – – >80% stay in similar 87.2% r government-subsidized housing e
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