2. Perhaps the single most important observation made in the twentieth century related to the origins of complex adult onset disorders was made by Barker and his colleagues ORIGIN OF COMPLEX ADULT ONSET DISEASES Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease . Lancet 1989;2:577–80.

3. “ Two decades ago, a British physician named David Barker noticed an odd correlation on a map: the poorest regions of England and Wales were the ones with the highest rates of heart disease. Why would this be, he wondered, when heart disease was supposed to be a condition of affluence — of sedentary lifestyles and rich food? He decided to investigate, and after comparing the adult health of some 15,000 individuals with their birth weight, he discovered an unexpected link between small birth size (1921-25)— often an indication of poor prenatal nutrition — and heart disease in middle age (1968-78). Faced with an inadequate food supply, Barker conjectured, the fetus diverts nutrients to its most important organ, the brain, while skimping on other parts of its body — a debt that comes due decades later in the form of a weakened heart .” Barker Hypothesis *

10. Fetal origins of non-insulin dependent diabetes D J P Barker BMJ 1995;311:171-4 *

12. may permanently affect ( fetal programming ) the structure and physiology of a range of organs and tissues, including the endocrine pancreas, liver, and blood vessels. Numerous animal experiments have shown that poor nutrition , and other influences that impair growth during critical periods of early life Winick M, J Nutr 1966 ; 89:300. Hahn P, J Nutr 1984 ; 114:1231. Pregnancy Possible explanations Barker DJP Lancet 1993;341:938

13. fetal programming directed by intrauterine signals that may optimize structure and function of organs in the in utero environment in the short run but contribute to disease in childhood and adulthood in the long run if these adaptations are mismatched with later environments ; may permanently affect ( fetal programming ) the structure and physiology of a range of organs and tissues, including the endocrine pancreas, liver, and blood vessels. Possible explanations Barker DJP Lancet 1993;341:938

25. This inverse relationship between birth weight and coronary artery disease death rates has been reproduced in populations from all continents (except Africa) Dover GJ. The Barker hypothesis: how pediatricans will diagnose and prevent common adult-onset diseases. Trans Am Clin Climatol Assoc. 2009;120:199-207.

27. Relation of birth weight to infant mortality and Complex Adult-Onset Disease Dover GJ. Trans Am Clin Climatol Assoc. 2009;120:199-207. 1 pound = 1lb = 453 g

29. Morbidities associated with intrauterine growth restriction (IUGR) can be split into metabolic and nonmetabolic effects Joss-Moore Curr Opin Pediatr. 2009; 21:230 + central adiposity = MS

32. Parental determinants of neonatal body composition. Harvey NC, J Clin Endocrinol Metab 2007;92:523. neonatal body composition in 448 births evaluated with dual-energy x-ray absorptiometry scan assessment of fat and muscle mass components of body composition in the offspring within 2 weeks of birth total fat mass was related to maternal lifestyle factors (smoking and physical activity) as well as maternal height, parity, and triceps skinfold thickness

33. Parental determinants of neonatal body composition. Harvey NC, J Clin Endocrinol Metab 2007;92:523. Maternal lifestyle and anthropometric factors and neonatal body composition

46. Blood Pressure

53. Type 2 diabetes

55. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. Aims/hypothesis: Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B12, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years.

58. contributes to childhood insulin resistance in humans imbalance in maternal vitamin B12 (low) and folate (high) status during pregnancy Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29.

59. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. Low vitamin B12 and erythrocyte folate concentrations were defined as <150 pmol/l and <283 nmol/l, respectively. Elevated total homocysteine (tHcy) and methylmalonic acid (MMA) concentrations were defined as >10 and >0.26 μmol/l

60. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Yajnik CS, Diabetologia 2008;51:29. We can only speculate about the possible mechanisms for our findings. Vitamin B12 deficiency will trap folate as 5-methyltetrahydrofolate, prevent the generation of methionine from homocysteine and therefore reduce protein synthesis and lean tissue deposition . Elevated methylmalonyl-CoA could contribute to increased lipogenesis by inhibiting carnitine palmitoyltransferase and thereby inhibit β-oxidation. An analogous clinical situation is high-dose folic acid treatment of severely vitamin B12-deficient pernicious anaemia patients: anaemia improves but neurological damage worsens, possibly because of accumulation of odd-chain carbon fatty acids.

61. Vitamin B12 , vitamin B12 or vitamin B-12 , also called cobalamin , is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Vitamin B12 is found in foods that come from animals, including fish and shellfish, meat (especially liver), poultry, eggs, milk, and milk products. Eggs are often mentioned as a good B12 source, but they also contain a factor that blocks absorption. While lacto-ovo vegetarians usually get enough B12 through consuming dairy products, vegans will lack B12 unless they consume multivitamin supplements or B12-fortified foods. Examples of fortified foods include fortified breakfast cereals, fortified soy products, fortified energy bars, and fortified nutritional yeast.

66. Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei Pediatrics 2010;125:899-905

67. Low Birth Weight and Lung Function in Adulthood: Retrospective Cohort Study in China, 1948–1996 Pei Pediatrics 2010;125:899-905 Lung function may be affected by hypogenesis in utero.

80. Regulation of cholesterol synthesis Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect . Cholesterol is a waxy steroid of fat that is manufactured in the liver or intestines to produce hormones and cell membranes and transported in the blood plasma of all mammals . [2] It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity . In addition, cholesterol is an important component for the manufacture of bile acids , steroid hormones , and Vitamin D .

82. The Sources of Mental Ilnesses “ At the farthest edge of fetal-origins research, scientists are exploring the possibility that intrauterine conditions influence not only our physical health but also our intelligence, temperament, even our psychological sanity ”. Annie M Paul Time October 4, 2010

86. Interpretation of the findings It has been known for many years that foetal growth is determined by the intra-uterine environment, specifically the ability of the mother to deliver nutrients. McCance, R. A. Proceedings of the Royal Society of London B, 1974;185:1-17 We postulate that male foetuses that are nutritionally stressed and grow slowly in utero are more likely to become depressed in adulthood. Female foetuses grow more slowly than males and therefore are less vulnerable at critical periods of development. Forsen, British Medical Journal, 1997;315: 837-840 Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455

87. Candidate mechanisms There are several mechanisms by which undernutrition of the foetus might cause permanent changes that increase later vulnerability to depression. Foremost among these is programming of the HPA axis . Small male babies have increased urinary adrenal androgen and glucocorticoid metabolite excretion at age 9 years ( Clark et al , 1996 ) and higher fasting cortisol concentrations as adults ( Philips et al , 1998 ). Raised plasma cortisol level is the most consistently demonstrated biological abnormality in primary depressive disorder ( Nemeroff et al , 1984 ; Murphy, 1991 ; Lopez et al , 1998 ). The growth hormone axis is another candidate. Median 24-h plasma growth hormone concentrations are related to weight at 1 year ( Fall et al , 1998 ), and in depression the control of growth hormone secretion is known to be disturbed. For example, growth hormone secretion in response to both clonidine ( Checkley et al , 1984 ) and slow wave sleep ( Sakkas et al , 1998 ) is reduced in patients with depression . Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455

88. Candidate mechanisms Thyroid function also may be set during foetal growth and infant feeding ( Philips et al , 1993 ) and reduced plasma thyrotropin levels coupled with impaired response to thyrotropin-releasing hormone ( Schule et al , 1997 ) are associated with depression ( Oomen et al , 1996 ). Although the brain is relatively protected during intra-uterine life, foetal undernutrition at critical periods can have neurodevelopmental effects — reducing cellular growth ( Winick et al , 1972 ), later IQ ( Davies & Stewart, 1975 ) and learning performance ( Katz, 1980 ). The effect on the serotonergic system has not been studied in any detail. Birth weight and the risk of depressive disorder in late life Thompson C. Br J Psychiatry 2001;179:450-455

115. Type 2 diabetes

116. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Dabelea D J Matern Fetal Med. 2000;9:83-8. OBJECTIVE: To review data on the long-term effects of prenatal exposure to the diabetic intrauterine environment in the Pima Indians of Arizona. This population has high rates of Type 2 diabetes mellitus that has a strong genetic component and develops at young ages. Quelli che vivono in Messico hanno un’incidenza del diabete pari circa all’8%, mentre quelli che sono emigrati negli Stati Uniti, dove lo stile di vita è più sedentario e l’accesso al cibo energetico (grasso) è più semplice, hanno un’incidenza di diabete che raggiunge il 50%.

121. An understanding of the role of gestational factors in disease can change individual behavior , notes Daniel Benyshek , a medical anthropologist at the University of Nevada at Las Vegas , who has interviewed members of Arizona's Native American tribes. He finds that those who believe diabetes is their genetic destiny tend to hold fatalistic attitudes about the illness. When Benyshek shared findings about the fetal origins of diabetes with tribe members, however, he noticed a different reaction. &quot;The idea that some simple changes made during pregnancy could reduce the offspring's risk for diabetes fosters a much more hopeful and engaged response,&quot; he says. &quot;Young women in particular are enthusiastic about the idea of intervening in pregnancy to break the cycle of diabetes. They say, 'I tried dieting , I tried exercising , and I couldn't keep it up. But I could do it for nine months if it meant that my baby would have a better chance at a healthy life.'&quot; Annie M Paul Time October 4, 2010

125. Diabetes risk begins in utero. Woo M, Patti ME. Cell Metab. 2008;8:5-7. Intrauterine stressors, including maternal undernutrition or placental dysfunction (leading to impaired blood flow, nutrient transport, or hypoxia) can initiate abnormal patterns of development and histone modification. Additional postnatal environmental factors, including accelerated postnatal growth, obesity, inactivity, and aging can further contribute to DM risk, potentially via further histone modifications and DNA methylation in critical tissues. Epigenetic events

129. Sleep-disorderd breathing or sleep deprivation during pregnancy

137. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Caldji C, Proc Natl Acad Sci USA 1998; 95:5335–5340. Mean±SEM time spent in exploration of the inner area of an open field in the adult offspring of high versus low LG-ABN mothers. correlation between maternal arched-back nursing and exploration. correlation between maternal licking/grooming and exploration. licking/grooming and arched-back nursing P<0.001

138. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Caldji C, Proc Natl Acad Sci USA 1998; 95:5335–5340. HIGH licking grooming Adult rats 90 days old

139. “ Mia will be an incredible swimmer” Uncle Grooming

142. This provides a biological basis for speculations about the effects of poverty on early experience, and how exposure to abuse , family strife , emotional neglect , and harsh discipline may have epigenetic effects that produce individual differences in neural and endocrine response to stress and may increase the susceptibility to common adult disorders such as depression and anxiety, drug abuse , and diabetes , heart disease , and obesity . From the Rat Model of Nurturing to the Child

156. Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Herrmann M, Curr Opin Pediatr 2008;20:184–190. effects of on child neurodevelopment. prenatal tobacco smoke exposure Low birth weight and decreased in-utero brain growth

157. Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Herrmann M, Curr Opin Pediatr 2008;20:184–190. effects of on child neurodevelopment. prenatal tobacco smoke exposure Low birth weight and decreased in-utero brain growth increased rates of: 1) irritability, 2) oppositional defiant behavior, 3) conduct disorders 4) attention deficit hyperactivity disorder.

158. CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 127 EXPOSED NON-EXPOSED P=0.01 Maternal Smoking during Pregnancy and Regional Brain Volumes in Preterm Infants Ekblad J Pediatr 2010;156:185 Magnetic Resonance

159. CEREBELLUM (mL) 23.1 24.5 EXPOSED NON-EXPOSED P=0.03 150 – 100 – 50 – 0 25 – 20 – 15 – 10 – 5 – 0 FRONTAL LOBE (mL) 118 127 EXPOSED NON-EXPOSED P=0.01 Maternal Smoking during Pregnancy and Regional Brain Volumes in Preterm Infants Ekblad J Pediatr 2010;156:185 Magnetic Resonance This is consistent with reports showing an association between prenatal smoking exposure and impairments in frontal lobe and cerebellar functions such as emotion, impulse control , and attention.

161. Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke Strulovici-Barel Am J Respir Crit Care Med 2011;182:1524 Rationale: Epidemiologic data demonstrate that individuals exposed to low levels of tobacco smoke have decrements in lung function and higher risk for lung disease compared with unexposed individuals. Although this risk is small, low-level tobacco smoke exposure is so widespread, it is a significant public health concern.

165. Indoor Pollution during Pregancy and first years of life

169. spray detergents and atopy-asthma

174. Outdoor Pollution during pregnancy

175. The Impact of Air The chance of a healthier life is what Frederica Perera is trying to give children in some of New York City's struggling neighborhoods. Perera, the director of the Center for Children's Environmental Health at Columbia University , became interested in the effects of pollution on fetuses more than 30 years ago , when she was conducting research on environmental exposures and cancer in adults. &quot;I was looking for control subjects to compare to the adults in my study, individuals who would be completely untouched by pollution,&quot; she says. She hit on the idea of using babies just out of the womb as her controls , but when she received the results from samples of umbilical-cord blood and placental tissue she'd sent to a laboratory to be analyzed, she was sure there had been a mistake. &quot;I was shocked,&quot; she says. &quot;These samples I thought would be pristine already had evidence of contamination.“ Annie M Paul Time October 4, 2010

182. Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. Whyatt RM, Environ Health Perspect. 1998;106 Suppl 3:821-6. * p≤0.05 White blood cell PAH-DNA adducts by level of air pollution = newborn

188. The Impact of Air &quot;We used to worry about elderly people and asthma patients,&quot; Perera says. &quot;Now we worry about fetuses.&quot; And efforts to reduce environmental toxins can make a measurable difference, she says. &quot;Over the years that we've been tracking exposures, New York City buses have switched to cleaner technology , and restrictions have been placed on the idling of diesel buses and trucks,&quot; Perera notes. &quot; As a result , we've seen the levels of pollutants in pregnant women's blood coming down , which means their fetuses are encountering fewer of these substances too.&quot; Annie M Paul Time October 4, 2010

189. Diet of the mother diuring pregnancy

191. Modulation of the