Effects of ethanol on photoreceptors and visual function in developing zebrafish

PURPOSE. Children born to mothers who have consumed alcohol during pregnancy have an array of retinal abnormalities and visual dysfunctions. In the past, rodent systems have been used to study the teratogenic effects of ethanol on vertebrate embryonic development. The exact developmental windows in which ethanol causes specific developmental defects have been difficult to determine because rodents and other mammals develop in utero. In this study, we characterized how ethanol affects the function and development of the visual system in an ex utero embryonic system, the zebrafish. METHODS. Zebrafish embryos were raised in fish water containing various concentrations of ethanol from 2 to 5 days after fertilization. The effects of ethanol on retinal morphology were assessed by histologic and immunohistochemical analyses and those on retinal function were analyzed by optokinetic response (OKR) and electroretinography (ERG). RESULTS. Zebrafish embryos exposed to moderate and high levels of ethanol during early embryonic development had morphological abnormalities of the eye characterized by hypoplasia of the optic nerve and inhibition of photoreceptor outer segment growth. Ethanol treatment also caused an increased visual threshold as measured by the OKR. Analysis with the ERG indicated that there was a severe reduction of both the a-and b-waves, suggesting that ethanol affects the function of the photoreceptors. Indeed, low levels of ethanol that did not cause obvious morphologic changes in either the body or retina did affect both the OKR visual threshold and the a-and b-wave amplitudes. CONCLUSIONS. Ethanol affects photoreceptor function at low concentrations that do not disturb retinal morphology. Higher levels of ethanol inhibit photoreceptor development and cause hypoplasia of the optic nerve. (Invest Ophthalmol Vis Sci. 2006;47:4589 -4597) DOI:10.1167/iovs.05-0971 S ome children born to mothers who have consumed alcohol during pregnancy have a number of morphologic, sensory, and cognitive abnormalities, including vision deficits, collectively known as fetal alcohol syndrome (FAS). It was originally thought that FAS was the result of alcohol abuse; however, smaller doses or shorter durations of prenatal alcohol consumption also produce harmful, though more subtle, effects referred to as alcohol-related birth defects (ARBDs) or alcoholrelated neurodevelopment disorder (ARND). 1 Even though FAS was described several decades ago, 2 little is known about the mechanistic underpinnings of ethanol teratogenicity. 3 The retina is one of the organs affected by ethanol during embryogenesis. As many as 90% of children in whom FAS is diagnosed have some type of ocular problem, ranging from microphthalmia and retinal dysmorphologies to reduced visual function. One of the challenges of analyzing ethanol's teratogenicity in vertebrates using rodents as model systems is that mammals develop in utero. Therefore, ethanol concentrations and exposure times that result in a specific phenotype are difficult to determine because the metabolic function of the mother must be considered. Other vertebrates, such as zebrafish and Xenopus laevis, develop ex utero, so specific concentrations of ethanol over specific developmental periods are easily achieved. Treating zebrafish and Xenopus embryos with ethanol results in phenotypes comparable to those described for children with FAS, suggesting that the same molecular mechanisms are disturbed by ethanol treatment in vertebrates. 9 -11 Moreover, unlike mouse, zebrafish contain abundant cone photoreceptors that differentiate relatively early, making it a better system for the study of color vision in vertebrates. MATERIALS AND METHODS Breeding Fish and Treating Zebrafish Embryos with Ethanol Ekkwill and AB strain zebrafish were maintained as an inbred stock at the Harvard zebrafish facility and were bred as previously described

Contribution of the neighborhood environment to cross-sectional variation in long-term CVD risk scores in the Framingham Heart Study.

Few studies of the health impact of the built environment have examined downstream outcomes, such as cardiovascular disease. We analyzed the neighborhood-level proportional variance in the 10- and 30-year Framingham risk scores (FRS) in the Framingham Heart Study. Our analysis included 3,103 Offspring- and Generation 3 cohort participants 20-74 years old, inhabiting private residences in Massachusetts geocoded to neighborhoods (defined as 2000 US Census block groups) containing the residences of ≥5 participants. The outcome variables were log-transformed to mitigate the effects of the non-normal distributions. In order to remove the possible effects of neighborhood clustering by age and sex, we analyzed residuals of the transformed FRS regressed upon age and sex. Neighborhood-level intraclass correlations (ICCs) and 95% confidence intervals (CIs) of age- and sex-independent, log-transformed FRS were estimated using multilevel linear regression. Individual- and neighborhood-level variables were then added to models to evaluate their influence on ICCs. Analyses were repeated stratified by sex. Among 2,888 participants living in 187 neighborhoods, 1.73% (95% CI: 0.62, 4.72%) of the variance in 10-year FRS was explained at the neighborhood level. The neighborhood ICC was 2.70% (95% CI: 0.93, 7.56) among women but 0.23% (95% CI: 0.00, 99.47%) among men. In the analysis of the neighborhood-level variances in 30-year FRS among 2,317 participants residing in 164 neighborhoods, the ICCs were 3.31% (95% CI: 1.66, 6.47%), 6.47% (95% CI: 3.22, 12.58), and 0.74% (95% CI: 0.01, 33.31), among all participants, women, and men, respectively. In our homogenous middle-class white population in Massachusetts, residential neighborhoods explained a small proportion of the variance in CVD risk

Characteristics of framingham offspring and generation 3 participants at offspring cohort examination 7 (1998–2001)/generation 3 examination 1 (2002–2005).

<p>Characteristics of framingham offspring and generation 3 participants at offspring cohort examination 7 (1998–2001)/generation 3 examination 1 (2002–2005).</p

Association of variability in body mass index and metabolic health with cardiometabolic disease risk

Background-Metabolic syndrome is associated with high risk of cardiovascular disease, although risk may differ according to the specific conditions present and variability in those conditions. Methods and Results-We defined obesity (body mass index [BMI] ≥30 kg/m 2 ) and metabolic health (<2 nonobesity National Cholesterol Education Program Adult Treatment Panel III conditions) among 3632 Framingham Heart Study offspring cohort participants (mean age, 50.8 years; 53.8% women) who were followed up from 1987 to 2014. We defined participants whose variance independent of the mean for a metabolic syndrome-associated measure was in the top quintile as being “variable” for that measure. Variable metabolic health was defined as ≥2 variable nonobesity metabolic syndrome components. We investigated the interaction between obesity and metabolic health in their associations with cardiometabolic disease and cardiovascular disease using Cox proportional hazards regression. In addition, we estimated the associations of BMI variability and variable metabolic health with study outcomes within categories of obesity and metabolic health status, respectively. We observed 567 incident obesity (41 439 person-years), 771 incident metabolically unhealthy state (25 765 person-years), 272 incident diabetes mellitus (56 233 person-years), 503 incident hypertension (12 957 person-years), 589 cardiovascular disease (60 300 person-years), and 195 chronic kidney disease (47 370 person-years) events on follow-up. Obesity and being metabolically unhealthy were independently and positively associated with all outcomes. BMI variability, compared with stable BMI, was associated with 163%, 67%, 58%, and 74% higher risks of having obesity, becoming metabolically unhealthy, having diabetes mellitus, and having hypertension, respectively, among nonobese participants. Variable metabolic health, compared with stable metabolic health, was associated with a 28% higher risk of cardiovascular disease, among metabolically healthy participants. Conclusions-We did not observe evidence for a positive interaction between obesity and metabolic health status with regard to study outcomes. BMI and metabolic health variability are associated with adverse health outcomes

Association of variability in body mass index and metabolic health with cardiometabolic disease risk

\u3cp\u3e Background-Metabolic syndrome is associated with high risk of cardiovascular disease, although risk may differ according to the specific conditions present and variability in those conditions. Methods and Results-We defined obesity (body mass index [BMI] ≥30 kg/m \u3csup\u3e2\u3c/sup\u3e ) and metabolic health (&lt;2 nonobesity National Cholesterol Education Program Adult Treatment Panel III conditions) among 3632 Framingham Heart Study offspring cohort participants (mean age, 50.8 years; 53.8% women) who were followed up from 1987 to 2014. We defined participants whose variance independent of the mean for a metabolic syndrome-associated measure was in the top quintile as being “variable” for that measure. Variable metabolic health was defined as ≥2 variable nonobesity metabolic syndrome components. We investigated the interaction between obesity and metabolic health in their associations with cardiometabolic disease and cardiovascular disease using Cox proportional hazards regression. In addition, we estimated the associations of BMI variability and variable metabolic health with study outcomes within categories of obesity and metabolic health status, respectively. We observed 567 incident obesity (41 439 person-years), 771 incident metabolically unhealthy state (25 765 person-years), 272 incident diabetes mellitus (56 233 person-years), 503 incident hypertension (12 957 person-years), 589 cardiovascular disease (60 300 person-years), and 195 chronic kidney disease (47 370 person-years) events on follow-up. Obesity and being metabolically unhealthy were independently and positively associated with all outcomes. BMI variability, compared with stable BMI, was associated with 163%, 67%, 58%, and 74% higher risks of having obesity, becoming metabolically unhealthy, having diabetes mellitus, and having hypertension, respectively, among nonobese participants. Variable metabolic health, compared with stable metabolic health, was associated with a 28% higher risk of cardiovascular disease, among metabolically healthy participants. Conclusions-We did not observe evidence for a positive interaction between obesity and metabolic health status with regard to study outcomes. BMI and metabolic health variability are associated with adverse health outcomes. \u3c/p\u3

Pregnancy outcomes and risk of endometrial cancer:A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16,986 women with endometrial cancer and 39,538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (OR) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR=0.59, 95% confidence interval (CI) 0.56–0.63). The risk reduction appeared greatest for the first full-term pregnancy (OR=0.78, 95%CI 0.72–0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR=0.20, 95%CI 0.14–0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7–9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy