Background:Early life is critical in mammary carcinogenesis and, thus, prevention efforts are increasingly shifting focus to examining youth.Obesity and chronic stress exposures (adverse life events, low socioeconomic status) are independently associated with early pubertal development that increases subsequent breast cancer risk.Specific Aims:In a multiethnic cohort of 443 girls, aged 6-7 at baseline, and followed for 2 years to date: 1. Determine the strength of the associations among chronic stress, visceral fat, early breast development (thelarche) and menarche. 2. Address unresolved questions about potential mediators of the link among chronic stress, visceral adiposity and the timing of thelarche and menarche.Methods:The proposed study builds on an established prospective epidemiological observational study of environmental determinants of puberty and breast cancer risk (n=443) (PI: Dr. Larry Kushi, Kaiser Permanente Northern California), which is a part of the NIH-funded Bay Area Breast Cancer and the Environment Research Center (PI: Dr. Robert Hiatt). Participants are recruited concurrently at sites in Cincinnati and New York, providing an opportunity to expand analyses across sites (N greater than 1200).Implications:The proposed study is poised to advance the field of breast cancer prevention by being the first to longitudinally examine associations among stress, obesity and pubertal timing. The findings of this study will help inform interventions targeting modifiable factors such as physical activity and diet in order to prevent obesity and delay puberty. Such interventions constitute a promising strategy for primary prevention of breast cancer.

No outline recieved

Background: Childhood allergy and sibship

There is consistent and strong evidence that the prevalence of atopy and hayfever are lower in children from large families or of higher birth orders1. The pattern is less consistent for childhood asthma, probably because its phentoype is less specific and easily confused with infection-related and other forms of non-atopic wheeze.

Sibship size and birth order are inevitably correlated - especially where average families are small - and it is not always easy to examine their independent effects. The apparent protection offered by increasing family size was originally ascribed to variations in the rates of early childhood infection and thus formed the basis for the 'hygiene hypothesis'2. This remains the most plausible and parsimonious explanation for much of the epidemiology of childhood allergy; but it does not preclude additional mechanisms related to birth order. For example, two studies of UK populations, separated in age by about 30 years, were unable to account for birth order effects by examination of recorded infections in early childhood3;4.

Within representative cohorts of families living in Ashford (Kent), Barcelona and Menorca we originally observed, on cross-sectional analysis, that mothers - but not fathers - who have given birth to more children are less often atopic. This relationship was not explained by maternal age5. Subsequently and prospectively, within the Ashford population, we reported that over seven years the loss of maternal atopy and hayfever are associated with a higher number of intervening pregnancies6.

One explanation for these observations is that they reflect changes in maternal and consequently maternal-foetal immunology with successive pregnancies, and that this in turn influences risk of allergic disease in the offspring. If this were the case one might expect to see a relation between parity and cord IgE. The observation that the birth order effect may be stronger if older siblings are male7, could reflect stronger immune responses of the mother to male compared to female foetuses. If maternal-foetal immunology is important, then one might expect a mother's change of partner to influence the birth order effect and for a child with older sibs born to a new father to have the same risk of atopy as a first-born child. This is analogous to the risk of pre-eclampsia which is higher in first than in subsequent pregnancies, but reverts to the risk for primiparous women in later pregnancies if the mother changes partner.

30/10/2006

No outline received

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No outline received

Evidence increasingly suggests that mental health problems are associated with insults during critical times of brain development, and also by exposures over an individual's life course. These include in-utero exposures, which may lead to subtle neurobehavioral difficulties, and contextual exposures such as neighbourhood quality and quality of child-rearing environment. Much of the work in this area to date has focused on early life determinants of schizophrenia, and to a lesser extent depression and suicide. Further, there is a body of evidence relating birthweight to cognitive function in childhood, though a recent sibling-based analysis suggested that this association was driven by fixed familial factors such as background socioeconomic position and behaviours/exposures that are similar for all siblings within a family. (1)

However, there is relatively little work on the role of early alcohol exposure on the occurrence of a range of cognitive, behavioural and emotional difficulties. Exposure to alcohol consumption in pregnancy is an example of the effects of an exposure during a sensitive period. The teratogenic effects of alcohol causes a variety of adverse developmental outcomes including Foetal Alcohol Syndrome (FAS) and Foetal Alcohol Effects. (2) Whereas consistent excessive drinking in pregnancy is definitely associated with more severe symptoms, the evidence is unclear as to the impact of more moderate drinking exposure on milder forms of developmental outcomes. However concerns remains over the fact that even moderate consumption of alcohol in pregnancy may increase the risk of mild cognitive impairment, ADHD and learning and behavioural difficulties. (2) Finally there is emerging evidence pointing to an association between alcohol and tobacco use in pregnancy and the development of addictive behaviours, such as addiction to alcohol. (3-6)

The mechanisms underlying these associations are unknown. It is assumed that the effects are due to specific intrauterine exposure, but genetic factors and shared familial factors (including socioeconomic position, shared/learnt familiar behaviours) may well explain any link between moderate alcohol consumption in pregnancy and later effects on offspring cognitive function and behaviour. One way to further explore this would be to compare associations of maternal alcohol consumption during pregnancy with offspring outcomes to the same associations with paternal alcohol consumption. To date no previous study has done this.

There are only a handful of studies with the capacity to test the early development of alcohol problems in children. Further evidence is needed to assess whether in-utero exposure to moderate alcohol consumption truly contributes to later developmental problems. If this is so it is also important to understand the mechanisms underlying these associations.

The aim of this proposal is to use ALSPAC data in order to determine whether intra-uterine exposure to alcohol consumption (assessed by maternal self-report of alcohol consumption during pregnancy) is related to poorer cognitive function, academic difficulties, behavioural problems (eg Attention Deficit Hyperactivity Disorders) during the childhood years and addictive behaviours later in adolescence. The association of maternal alcohol consumption during pregnancy with these offspring outcomes will be compared to similar associations with paternal alcohol consumption (based on self-report by the partner of the mother with restriction to those who define themselves as the biological father). This comparison will facilitate our ability to determine whether there is a true intrauterine effect, since if there is one would anticipate associations only with maternal alcohol consumption. Similar association with paternal intake would suggest that genetic factors and/or shared family environmental factors explain the association rather than specific intrauterine effects.

No outline received