High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring.
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ABSTRACT:
SUBMITTER: de Assis S
PROVIDER: S-EPMC3570979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Maternal exposures during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. We investigated whether feeding pregnant rats a high fat (HF) or ethinyl-estradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. Here we show that mammary tumorigenesis is higher in daughters and granddaughters of HF rat dams and in daughters, granddaughters and great-granddaughters of EE2 rat dams. Outcross experiments indicate that increased mammary cancer risk is transmitted to HF granddaughters equally through the female or male germlines, but it is only transmitted to EE2 granddaughters through the female germline. The effects of maternal EE2 exposure on offspring's mammary cancer risk are associated with alternations in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and estrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through non-genetic means
2012-09-20 | GSE40251 | GEO
Project description:Maternal exposures during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. We investigated whether feeding pregnant rats a high fat (HF) or ethinyl-estradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. Here we show that mammary tumorigenesis is higher in daughters and granddaughters of HF rat dams and in daughters, granddaughters and great-granddaughters of EE2 rat dams. Outcross experiments indicate that increased mammary cancer risk is transmitted to HF granddaughters equally through the female or male germlines, but it is only transmitted to EE2 granddaughters through the female germline. The effects of maternal EE2 exposure on offspring's mammary cancer risk are associated with alternations in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and estrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through non-genetic means We examined the whole genome methylation status of both control and EE2-supplemented diet rats in three consecutive generations
2012-09-20 | E-GEOD-40251 | biostudies-arrayexpress
Project description:Mechanisms underlying modern increases in prevalence of human inflammatory diseases remain unclear. The hygiene hypothesis postulates that decreased microbial exposure has, in part, driven this immune dysregulation. However, dietary fatty acids also influence immunity, partially through modulation of responses to microbes. Prior reports have described the direct effects of high-fat diets on the gut microbiome and inflammation, and some have additionally shown metabolic consequences for offspring. Our study sought to expand on these previous observations to identify the effects of parental diet on offspring immunity using mouse models to provide insights into challenging aspects of human health. To test the hypothesis that parental dietary fat consumption during gestation and lactation influences offspring immunity, we compared pups of mice fed either a Western diet (WD) fatty acid profile or a standard low-fat diet. All pups were weaned onto the control diet to specifically test the effects of early developmental fat exposure on immune development. Pups from WD breeders were not obese or diabetic, but still had worse outcomes in models of infection, autoimmunity, and allergic sensitization. They had heightened colonic inflammatory responses, with increased circulating bacterial LPS and muted systemic LPS responsiveness. These deleterious impacts of the WD were associated with alterations of the offspring gut microbiome. These results indicate that parental fat consumption can leave a "lard legacy" impacting offspring immunity and suggest inheritable microbiota may contribute to the modern patterns of human health and disease.
| S-EPMC3831371 | biostudies-literature
Project description:BackgroundThe effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined.MethodsThe body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI).ResultsBMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2 ). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values.ConclusionIntrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.
| S-EPMC8497931 | biostudies-literature
Project description:Maternal or paternal high fat (HF) diet can modify the epigenome in germ cells and fetal somatic cells leading to an increased susceptibility among female offspring of multiple generations to develop breast cancer. We determined if combined treatment with broad spectrum DNA methyltransferase (DNMT) inhibitor hydralazine and histone deacetylase (HDAC) inhibitor valproic acid (VPA) will reverse this increased risk. C57BL/6 mouse dams were fed either a corn oil-based HF or control diet during pregnancy. Starting at age 7 weeks, female offspring were administered 3 doses of 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary cancer. After last dose, offspring started receiving VPA/hydralazine administered via drinking water: no adverse health effects were detected. VPA/hydralazine reduced mammary tumor multiplicity and lengthened tumor latency in HF offspring when compared with non-treated HF offspring. The drug combination inhibited DNMT3a protein levels and increased expression of the tumor suppressor gene Cdkn2a/p16 in mammary tumors of HF offspring. In control mice not exposed to HF diet in utero, VPA/hydralazine increased mammary tumor incidence and burden, and elevated expression of the unfolded protein response and autophagy genes, including HIF-1?, NFkB, PERK, and SQSTM1/p62. Expression of these genes was already upregulated in HF offspring prior to VPA/hydralazine treatment. These findings suggest that breast cancer prevention strategies with HDAC/DNMT inhibitors need to be individually tailored.
| S-EPMC6937280 | biostudies-literature
Project description:Stressors during the fetal and postnatal period affect the growth and developmental trajectories of offspring, causing lasting effects on physiologic regulatory systems. Here, we tested whether reduced uterine artery blood flow in late pregnancy would alter body composition in the offspring, and whether feeding offspring a western diet (WD) would aggravate these programming effects. Pregnant rats underwent bilateral uterine artery ligation (BUAL) or sham surgery on gestational day (GD)18 (term = GD22). At weaning, offspring from each group received either a normal diet (ND) or a WD. BUAL surgery increased fetal loss and caused offspring growth restriction, albeit body weights were no longer different at weaning, suggesting postnatal catch-up growth. BUAL did not affect body weight gain, fat accumulation, or plasma lipid profile in adult male offspring. In contrast, while ND-fed females from BUAL group were smaller and leaner than their sham-littermates, WD consumption resulted in excess weight gain, fat accumulation, and visceral adiposity. Moreover, WD increased plasma triglycerides and cholesterol in the BUAL-treated female offspring without any effect on sham littermates. These results demonstrate that reduced uterine artery blood flow during late pregnancy in rodents can impact body composition in the offspring in a sex-dependent manner, and these effects may be exacerbated by postnatal chronic WD consumption.
| S-EPMC7181802 | biostudies-literature
Project description:The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers' serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.
| S-EPMC7203245 | biostudies-literature
Project description:Maternal high fat diet (HFD) and obesity during pregnancy increase female offspring's mammary cancer risk in animal studies. We aimed to observe whether the consumption of grape juice during pregnancy can reverse this risk. During pregnancy and lactation, female Wistar rats were fed either a control or HFD and also received grape juice or tap water. At the age of 50 days, female offspring were euthanized, and mammary glands were collected to assess changes in biomarkers of increased mammary cancer risk. Maternal HFD increased the number of terminal end buds in offspring's mammary glands and promoted cell proliferation (ki67). Maternal grape consumption blocked these effects. Apoptosis marker caspase 7, but not caspase 3, was reduced in the HFD offspring. HFD offspring also exhibited a reduction in the indicators of cell cycle regulation (p27, p21) and an ability to maintain DNA integrity (reduced p53). Maternal grape juice did not have any effect on these endpoints in the HFD offspring but reduced caspase 7 and p53 levels in the control offspring, perhaps reflecting reduced cellular stress. Maternal HFD increased oxidative stress marker GPx1 mRNA expression, and grape juice increased the levels of GPx2 in both the control and HFD offspring. HFD increased XBP1/Xbp1s, Atf4 and Atf6 mRNA expression and reduced ATF6 and CHOP protein levels. Maternal grape juice reversed the increase in XBP1/Xbp1s, Atf4 and Atf6 in the HFD offspring. PPAR was downregulated in the HFD group, and grape juice reversed this effect. Grape juice also reduced the levels of HER2 and IRS, both in the control and HFD offspring. In conclusion, maternal grape juice supplementation reversed some of the biomarkers that are indicative of increased breast cancer risk in the HFD offspring.
| S-EPMC7547380 | biostudies-literature
Project description:BackgroundObservational and experimental evidence demonstrates that protein intake in infancy programs linear growth. To our knowledge, few studies have examined prenatal maternal protein intake.ObjectiveOur objective was to examine associations of maternal protein intake during pregnancy with offspring linear growth.DesignWe analyzed data from 1961 mother-child pairs in Project Viva. We assessed first- and second-trimester diet with the use of food-frequency questionnaires and analyzed protein intake as grams per kilogram prepregnancy weight per day. We used research measures of offspring length at birth and in infancy (∼6 mo), early childhood (∼3 y), and midchildhood (∼7 y), as well as clinical growth measures obtained from after birth through midchildhood. We calculated sex-specific birth length z scores for gestational age with the use of international reference data. We used mixed models with repeated length measures to predict individual length gain velocities for birth to <6 mo and 6 mo to 7 y of age, then used these velocities as outcomes in adjusted linear regression models with maternal protein intake as the main predictor.ResultsMean (range) second-trimester protein intake was 1.4 g · kg-1 · d-1 (0.3-3.1 g · kg-1 · d-1). After adjusting for maternal sociodemographics, gestational weight gain, maternal and paternal height, and (for postdelivery outcomes) child sex, gestational age, and breastfeeding duration, each 1-SD (0.36 g · kg-1 · d-1) increment in second-trimester protein intake corresponded to a -0.10 (95% CI: -0.18, -0.03) change in birth length z score, a -0.03 cm/mo (95% CI: -0.05, -0.01 cm/mo) change in slope of length growth from birth to <6mo, and a -0.09 cm/y (95% CI: -0.14, -0.05 cm/y) change in slope of length growth from 6 mo to midchildhood. Results were similar for first-trimester intake.ConclusionsIn a population with relatively high protein intake during pregnancy, higher protein intake was associated with shorter offspring birth length and slower linear growth into midchildhood. Results suggest that higher protein intake during pregnancy does not increase fetal and child growth and may even reduce early length growth. Project Viva was registered at clinicaltrials.gov as NCT02820402.
| S-EPMC5039807 | biostudies-literature
Project description:Ethinyl estradiol (EE) is a synthetic estrogen used in pharmaceutical contraceptives. In many studies evaluating estrogenic endocrine disruptors, EE is used as a positive control for estrogenicity. However, the effects of EE often differ from the effects of other xenoestrogens, suggesting that these other compounds might act via distinct mechanisms. Reported here are data describing the effect of low doses of EE during pregnancy and lactation on the morphology of the lactating mammary gland in CD-1 mice. The data suggest that these low doses have few if any discernable effects on mammary gland morphology. Alterations to cell proliferation and the expression of estrogen receptor (ER)? were also not observed. These companion data were collected from the same females analyzed for effects of EE on maternal behavior and brain recently published in Reproductive Toxicology (Catanese & Vandenberg, 2017).
| S-EPMC5547231 | biostudies-literature