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Life course approach is key in cancer prevention • Cancer process takes decades, there may be as much as 40 years between first assault and diagnosis • Cancer biology may be determined in very early life (eg maternal hormones & vaginal cancer in offspring; early diet and carcinogen exposure, birth weight, early growth, dietary Diet, Nutrition and theheight, Life Courseobesity, Approach tobreast Cancer Prevention preferences, attained feeding etc) • Adult diet and PA behaviors are established in early life • Early life is most sensitive to cancer inducing processes (eg, relatively high cancer risk in under tens exposed to radiation or carcinogens; smoking in adolescence) R. Uauy MD.PhD LSHTM/UK, INTA/UCHILE/IUNS/past President Annual Cancer Rates 1970-1996 all races (rates per 100,000) Males ——— Females — — — P. Perera Science 1997 278:1068 polycyclic aromatic Hydrocarbons PAH Cancer Environment Susceptibility Genes P450, glutathione S-transferase (GST) N-acetyltransferase (NAT) Cancer prevention : a Life Course Approach Development of Cancer Infancy and Childhood Adolescence Adult Life Older ages Fetal Life Accumulated risk Genetic susceptibility to Cancer Age Diet, Nutrition and Life Course Approach to Cancer Prevention • Nutrients and toxicants from food and water constitute important life time exposures that contribute to cancer risk • Diet as a determinant of growth & body composition affects risk • Directly by cumulative exposure to carcinogens in foods, Indirectly by affecting rates of tissue growth and body composition and by inducing hormonal/metabolic/ inflammatory responses that affect the cancer process. • Obesity and rapid weight gain as cancer risk factors; Enhanced linear growth may also affect risk for some cancers. • Food preferences and activity patterns become set relatively early in life; leading to adoption of healthy or unhealthy habits Adenocarcinoma of the Vagina: Diethylstilbestrol (DES) therapy with tumor appearance in female offspring during adolescence In the late 1940s, 1950s, and later, DES was used as Rx in early pregnancy in the belief that it would decrease toxemia of pregnancy and bleeding and help to reduce the incidence of premature births and neonatal deaths This was the first documented instance where a prenatal drug exposure–induced cancer in humans Herbst AL et al Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881. 1971. Umbilical cord blood from newborns found an array of industrial chemicals, pesticides and pollutants. Ten newborns averaged 200 contaminants, and 209 pollutants had never before been detected in cord blood. Of the 287 chemicals found in newborn umbilical cord blood, 180 cause cancer in humans or animals, 217 are toxic to the brain and nervous system, and 208 cause developmental problems. The dangers of exposure to these chemicals in combination has never been studied. Endocrine disruptors during breast development Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. TCDD a prototypical endocrine-disrupting compound, 2,3,7,8tetra chloro dibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation/differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection. Birnbaum SL Environ Health Perspect 111:389–394 (2003). Endocrine disruptors during breast development Control ATR 100mg/kg atrazine TCDD 1 µg/kg dioxin PND 4 PND 33 PND 68 Mammary gland tissue from LE rats exposed in late gestation to ATR is atrazine ( a pesticide) and TCDD or 2,3,7,8-tetrachlorodibenzo-p dioxin. Birnbaum SL Environ Health Perspect 111:389–394 (2003). PRODUCE: Pesticides used on many crops also act as endocrine-disruptors, increasing risks for cancer as well as neurodevelopmental disorders PERSONAL CARE PRODUCTS: Many lotions and cosmetics contain phthalates and chemicals that may be absorbed across the skin. LANDSCAPING: Exposure to chemicals used on lawns, gardens, playgrounds, and athletic fields may increase risk for cancer LONG-TERM EXPOSURE: Young children and teens may be particularly susceptible to long-term effects of exposure to chemicals because of the rapid changes their bodies are undergoing. PLASTICS: Additives may leach out of the plastics when they are heated or when children chew on some toys. GRILLED MEATS: Grilled meats, cigarette smoke and automobile exhaust, all contain polycyclic aromatic carbons (PAHs), which are potential carcinogens. The use of Bisphenol A (BPA) in bottles and other food packaging continues to stir controversy, with calls from a UK-based pregnancy charity for mandatory labelling of the chemical present in packs. The National Childbirth Trust (NCT) says that a clear labelling system, particularly on infant feeding bottles, should be introduced over fears that the chemical can leak into beverages and food. Some recent animal studies have indicated that high levels of BPA could be carcinogenic. European Food Safety Authority (EFSA) policy permitting a maximum daily intake of 0.05 milligram/kg body weight. US NIH/ National Institute of Environmental Health Sciences recommends: • Don't microwave polycarbonate plastic food containers. Poly carbonate is strong and durable, but over time it may break down from over use at high temperatures. • Polycarbonate containers that contain BPA usually have a #7 on the bottom. • Reduce your use of canned foods. • When possible, opt for glass, porcelain or stainless steel containers, particularly for hot food or liquids. • Use baby bottles that are BPA free. USA National Toxicology Program Brief on Bisphenol A [CAS No. 80-05-7]. Published April 14, 2008. Diet, Nutrition and Life Course Approach to Cancer Prevention • Nutrients and toxicants from food and water constitute important life time exposures that contribute to the risk of some cancers • Diet as a determinant of growth & body composition affects risk Directly by the cumulative effect of exposure to carcinogens in foods, Indirectly by the hormonal/metabolic responses to growth or the inflammatory response associated the metabolic syndrome. • Obesity and rapid weight gain as cancer risk factors; enhanced linear growth may also affect cancer risk • Food preferences and physical activity patterns become set relatively early in life; leading to adoption of healthy or unhealthy habits Birth Weight and Breast Cancer Risk I dos Santos et al PLOS Med 5: e19308 Birth Weight Increment and Breast Cancer Risk I dos Santos et al PLOS Med 5: e19308 Birth Length Increment and Breast Cancer Risk I dos Santos et al PLOS Med 5: e19308 Health effects of breastfeeding I • Breastfeeding has positive health effects, the largest health gain are realized through policies that encourages all mothers to breastfeed. • The literature review shows that breastfeeding has both short and the longer term beneficial health effects • There is convincing evidence that the incidence obesity is reduced in breastfed children. • Probable evidence that breastfed children have enhanced intellectual and motor development. • Probable Breastfeeding is related to a reduction of type I diabetes mellitus and leukaemia. CTM van Rossum, et al Quantification of health effects of breastfeeding RIVM report 350040001/05 CTM van Rossum, et al Quantification of health effects of breastfeeding RIVM report 350040001/05 1. “How o(en does your baby drink all of his or her bo7le of formula?” 2. “How o(en does your baby drink all of his or her cup or bo7le of pumped milk?” 3. “How o(en is your baby encouraged to finish a bo7le if he or she stops drinking before the formula is all gone?” 4. “How o(en is your baby encouraged to finish a cup or bo7le if he or she stops drinking before the pumped breast milk is all gone?” “never,” “rarely,” “someEmes,” “most of the Eme,” or “always” Bivariate Analysis for AssociaEon Between Variables & Infants’ Risk of Having Excess Weight > 6 mo of age R Li, S Fein, L Grummer-‐Strawn Pediatrics 2008;122:S77–S84 Infants’ risk for excess weight during late infancy was negaEvely associated with breasWeeding intensity but posiEvely associated with infant-‐iniEated bo7le emptying during early infancy. These findings provide evidence for the potenEal risk of not breasWeeding or breasWeeding at a low intensity in development of childhood obesity, They also suggest that infant-‐iniEated bo7le emptying may be an independent risk factor for obesity as well. R Li, S Fein, L Grummer-‐Strawn Pediatrics 2008;122:S77–S84 Early Determinants of Fruit and Vegetable Acceptance Catherine A. Forestell, PhD, Julie A. Mennella, PhD Monell Chemical Senses Center, Philadelphia, Pennsylvania Examples of types of facial expressions displayed during the first 2 minutes of feeding: brow lowerer (A), inner brow raise (B), squint (C), nose wrinkle (D), upper-‐lip raise (E), and gape (F). www.pediatrics.org/cgi/doi/10.1542/ peds.2007-‐0858 doi:10.1542/peds.2007-‐0858 Distaste expression before and after 8 days of home-exposure. Fed only green beans Cumulative number per spoon offer Fed green beans + mothers reported eaRng fruits during the previous week peaches Peach consumption when first fed P < 0.05, compared with breastfed infants Mothers eating fruit prior week P < 0.05, compared with Lactating mothers mothers reported eaRng fruits during the previous week Distaste expression when first fed P < 0.05, compared with breastfed infants mothers reported eaRng fruits during the previous week BreasWeeding confers an advantage in iniEal acceptance of a food, but only if mothers eat the food regularly. Once weaned, infants repeatedly exposed to a food eat more of rieported t and may le earn to like its flavor. the mothers aRng fruits during eek of distaste Because infants dprevious isplay facial w expressions in response to certain flavors, caregivers may disconEnue offering these foods. Mothers should offer repeatedly fruits & vegetables www.pediatrics.org/cgi/doi/10.1542/peds.2007-‐0858 focusing on willingness to conEnue feeding. Growth and Obesity Cohort Study (GOCS): 1200 Chilean children a<ending public nursery schools in the year 2006 2002 -‐2003 0y 2006 3.5y 2007 4y GOCS I 2008 5.5y 2009 6.5y GOCS II 2500-‐4500gr n= 14330 n= 313 n= 1196 n= 1196 n= 1050 2012 9.5y Timing of adiposity rebound in 805 Chilean children born in 2002, by BMI status at 7y BMI kg/m2 BAZ >2 Timing of AR % <2y 52.7 2-‐4y 48.1 4-‐5y 1 <=BAZ <=2 5-‐7y 38.7 27.7 BAZ <1 25.0 24.8 20.7 22.6 18.9 10.5 8.6 1.7 Age (months) BMI Z-‐scores based on WHO 2007 Pre Pregnancy Pubertal Sexual maturation BMI Early Adiposity rebound Maternal Glucose Insulin Placental Fetal blood flow Hormonal responses Fetal growth restriction Fetal Macrosomia feeding fast Weight gain Central Obesity Metabolic syn Hormonal responses High BMI Obesity Breast Cancer — Early Life Matters Relation between height at 12 yrs of age among Japanese girls and breast cancer 30 yrs later in women 40 to 44 yrs Michels KB and Willett WC NEJM 351;16 (2004) % Cancer deaths attributable to environmental and behavioural factors in developed country setting Tobacco Food+water Infections Hormonal Natural radiation Alcohol Occupation Ultraviolet light Medical radiation 0 5 10 15 Percent 20 25 30 35 Doll and Peto, 1996 Peak exposure started stopped G. Marshall et al J NCI 99: 920–8 2007 Lung Cancer As related adult mortality according to timing of As exposure AMR=observed/expected age adjusted death rate Young adulthood infancy p < 0.001 p < 0.001 AMR AMR childhood p < 0.001 Middle age adulthood p < 0.001 G. Marshall et al J NCI 99: 920–8 2007 Conclusions This review suggests that the combination of specific exposures (environmental, nutritional or metabolic), hormonal responses related to accelerated growth at critical periods, adrenarchy, puberty and menarchy interacting with obesogenic diets may confer increased risk for some types of cancer. Therefore, modification in early life of diet, nutrition, growth, physical activity patterns and body composition may help to reduce this risk. Following-up biomarker profiles that predict cancer may increase the effectiveness of nutritional intervention since epi- and genetic variability affect timing of growth and endocrine responses related to cancer risk. Such approach should be part of a strategy to enhance effectiveness of interventions by focusing on reducing risk at critical time-windows in order to achieve greatest impact on cancer incidence. 1035 5746 Survival by Group Surgery vs Control Christou et al Annals of Surgery 240:416–424, 2004 Weight Loss, Bariatric Surgery Cohort n=1035 Christou et al Annals of Surgery 240:416–424, 2004 Five-Year Morbidity & Mortality (Cohort Surgery vs Control) Christou et al Annals of Surgery 240:416–424, 2004 L Sjöström et al,NEJM 357:741-52 2007. NUTRITIONALLY INDUCED EPIGENETIC IMPRINTING betaine choline folic acid vit B12. Yellow! Slightly Mottled Mottled Heavily Mottled Pseudo agouti Isogenic Avy/a animals representing five-coat colors used to classify phenotype. Avy mutation results from the insertion of a murine LTR retrotransposon into an exon of the agouti gene Avy hyper methylation silences ectopic Agouti expression in Pseudo-agouti animals, recapitulating the agouti phenotype. Waterland & Jirtle Nutrition20:1 2004 Difference in IGF2 DMR methylation between individuals prenatally exposed to famine and their same-sex sibling. Periconceptional exposure Exposure late in gestation Heijmansa BT et al PNAS 105:17046–17049 2008 Periconceptional exposure was defined as the mother’s last menstrual period before conceiving the exposed individual between November 28, 1944 and May 15, 1945. This yielded 60 sibships. Exposure late in gestation was defined as a birth between January 28 and May 30, 1945, so that the duration of the famine exposure was at least 10 weeks. This yielded 62 sibships. Individuals prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for peri conceptional exposure, reinforcing that very early development is a crucial period for establishing epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life. Heijmansa BT et al PNAS 105:17046–17049 2008 Conclusion—Our results show that in a population with a genetic tendency for obesity, effects of maternal obesity accumulate over successive generations to shift the population distribution toward increased adult body weight, and suggest that epigenetic mechanisms are involved in this process. Developmental Plasticity A single genotype can produce many ! phenotypes, depending on many contingencies! encountered during development. That is, ! phenotype is an outcome of a complex series of! developmental processes that are influenced by ! environmental factors as well as genes. ! H. F. Nijhout, 1999! Towards a new developmental synthesis:adaptive developmental plasticity and human disease Gluckman P ..... Uauy R et al Lancet 2009; 373:1654-7 Cancer prevention : a Life Course Approach Development of Cancer Infancy and Childhood Fetal Life SES Mother’s Nutrition Carcinogen Exposures Fetal Growth birth weight Breast Feeding SES Infections/PEM Micronutrients Contaminants (air, food, water,) Growth rate Stature Physical Activity Food and Play Behaviours Adolescence Smoking Contaminants (air, food, water,) Time of Puberty Obesity Exercise and Physical activity Inactivity Adult Life Older ages Established adult risky behaviours Diet/Physical activity, Tobacco, Alcohol, Carcinogens OBESITY Biological risks Socioeconomic status Environmental conditions Preventable risk Cumulative incidence Genetic susceptibility to Cancer Age Cancer prevention : a Life Course Approach Development of Cancer Infancy and Childhood Adolescence Adult Life Older ages Fetal Life Genetic susceptibility to Cancer Age Cancer prevention : a Life Course Approach Development of Cancer Infancy and Childhood Adolescence Adult Life Older ages Fetal Life IN THE IDEAL WORLD Genetic susceptibility to Cancer Age