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      Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine

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          Abstract

          We previously showed that maternal under-nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren. Historical cohort study. Web-based questionnaire. The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944-45 Dutch famine. We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire. Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure. Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m(2), P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups. Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under-nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future. © 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.

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          Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease.

          The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1-F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1-F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.
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            Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

            OBJECTIVE—Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F1-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy. RESEARCH DESIGN AND METHODS—We intercrossed female and male F1 adult control (C) and UN mice and characterized metabolic phenotypes in F2 offspring. RESULTS—We demonstrate that 1) reduced birth weight progresses to F2 offspring through the paternal line (C♀-C♂ = 1.64 g; C♀-UN♂ = 1.57 g, P < 0.05; UN♀-C♂ = 1.64 g; UN♀-UN♂ = 1.60 g, P < 0.05), 2) obesity progresses through the maternal line (percent body fat: C♀-C♂ = 22.4%; C♀-UN♂ = 22.9%; UN♀-C♂ = 25.9%, P < 0.05; UN♀-UN♂ = 27.5%, P < 0.05), and 3) IGT progresses through both parental lineages (glucose tolerance test area under curve C♀-C♂ = 100; C♀-UN♂ = 122, P < 0.05; UN♀-C♂ = 131, P < 0.05; UN♀-UN♂ = 151, P < 0.05). Mechanistically, IGT in both F1 and F2 generations is linked to impaired β-cell function, explained, in part, by dysregulation of Sur1 expression. CONCLUSIONS—Maternal undernutrition during pregnancy (F0) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).
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              Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile.

              Evidence from animal models suggests that fetal undernutrition can predispose to hypercholesterolemia and metabolic disorders directly by programming cholesterol metabolism and may indirectly influence lifestyle choices. We have shown that persons who were exposed to the Dutch famine in early gestation have a more atherogenic lipid profile. We now investigate whether the excess in hypercholesterolemia may be a result of a more atherogenic diet or a reduction in physical activity. We measured lipid profiles, dietary intake, and physical activity in 730 men and women (aged 58 y) born in the Wilhelmina Gasthuis in Amsterdam, Netherlands, around the time of the Dutch famine, whose birth records have been kept. No differences were observed in mean intake of total energy or percentage of protein, carbohydrate, and fat in the diet between the different exposure groups. However, persons exposed to famine in early gestation were twice as likely (odds ratio: 2.1; 95% CI: 1.2, 3.9) to consume a high-fat diet (defined as the highest quartile of percentage of fat in the diet: >39% of energy from fat). They also tended to be less physically active (45% did sports compared with 52% in the unexposed group), although this did not reach statistical significance. This is the first direct evidence in humans that prenatal nutrition may affect dietary preferences and may contribute to more atherogenic lipid profiles in later life.
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                Author and article information

                Journal
                BJOG: An International Journal of Obstetrics & Gynaecology
                BJOG
                Wiley
                14700328
                April 2013
                April 2013
                January 24 2013
                : 120
                : 5
                : 548-554
                Affiliations
                [1 ]Department of Clinical Epidemiology, Biostatistics and Bioinformatics; Academic Medical Centre; University of Amsterdam; Amsterdam; the Netherlands
                [2 ]Department of Obstetrics and Gynaecology; Academic Medical Centre; University of Amsterdam; Amsterdam; the Netherlands
                [3 ]Liggins Institute; University of Auckland; Auckland; New Zealand
                [4 ]Academic Unit of Human Development and Health; University of Southampton; Southampton; UK
                Article
                10.1111/1471-0528.12136
                23346894
                552609b6-2432-4bd3-8e50-15a16548841b
                © 2013

                http://doi.wiley.com/10.1002/tdm_license_1.1

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