scholarly journals Transgenerational effects of maternal bisphenol: a exposure on offspring metabolic health

2018 ◽  
Vol 10 (02) ◽  
pp. 164-175 ◽  
Author(s):  
A. Bansal ◽  
C. Li ◽  
F. Xin ◽  
A. Duemler ◽  
W. Li ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Bisphenol A ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Metabolic Health ◽  
Male Offspring ◽  
Exposure Model ◽  
Transgenerational Effects

AbstractExposure to the endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with health abnormalities that persist in subsequent generations. However, transgenerational effects of BPA on metabolic health are not widely studied. In a maternal C57BL/6J mice (F0) exposure model using BPA doses that are relevant to human exposure levels (10 μg/kg/day, LowerB; 10 mg/kg/day, UpperB), we showed male- and dose-specific effects on pancreatic islets of the first (F1) and second generation (F2) offspring relative to controls (7% corn oil diet; control). In this study, we determined the transgenerational effects (F3) of BPA on metabolic health and pancreatic islets in our model. Adult F3 LowerB and UpperB male offspring had increased body weight relative to Controls, however glucose tolerance was similar in the three groups. F3 LowerB, but not UpperB, males had reduced β-cell mass and smaller islets which was associated with increased glucose-stimulated insulin secretion. Similar to F1 and F2 BPA male offspring, staining for markers of T-cells and macrophages (CD3 and F4/80) was increased in pancreas of F3 LowerB and UpperB male offspring, which was associated with changes in cytokine levels. In contrast to F3 BPA males, LowerB and UpperB female offspring had comparable body weight, glucose tolerance and insulin secretion as Controls. Thus, maternal BPA exposure resulted in fewer metabolic defects in F3 than F1 and F2 offspring, and these were sex- and dose-specific.

scholarly journals Erratum to: “Dehydroepiandrosterone increases β-cell mass and improves the glucose-induced insulin secretion by pancreatic islets from aged rats” [FEBS Lett. 580 (2006) 285-290]

FEBS Letters ◽  
2006 ◽  
Vol 580 (5) ◽  
pp. 1528-1528
Author(s):  
Mayrin C. Medina ◽  
Lílian C. Souza ◽  
Luciana C. Caperuto ◽  
Gabriel F. Anhê ◽  
Angélica M. Amanso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Mass ◽  
Aged Rats ◽  
Β Cell

scholarly journals Deficiency of FcϵR1 Increases Body Weight Gain but Improves Glucose Tolerance in Diet-Induced Obese Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4047-4058 ◽  
Author(s):  
Yun-Jung Lee ◽  
Conglin Liu ◽  
Mengyang Liao ◽  
Galina K. Sukhova ◽  
Jun Shirakawa ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Body Weight Gain ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein

Prior studies demonstrated increased plasma IgE in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcϵR1-deficient (Fcer1a−/−) mice and diet-induced obesity (DIO) mice demonstrated that FcϵR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue from Fcer1a−/− mice showed an increased expression of phospho-AKT, CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ, glucose transporter-4 (Glut4), and B-cell lymphoma 2 (Bcl2) but reduced uncoupling protein 1 (UCP1) and phosphorylated c-Jun N-terminal kinase (JNK) expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake but induces energy expenditure, adipocyte apoptosis, and white adipose tissue inflammation. In 3T3-L1 cells, IgE inhibited the expression of CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ, and preadipocyte adipogenesis and induced adipocyte apoptosis. IgE reduced the 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a−/− mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.

scholarly journals Pre-Conception Weight Loss Improves Reproductive, Metabolic and Kidney Health in Obese Mice and Their Offspring

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A322-A323
Author(s):  
Natassia Rodrigo ◽  
Hui Chen ◽  
Carol Pollock ◽  
Sarah Glastras
Keyword(s):  
Chronic Kidney Disease ◽  
Weight Loss ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Inflammatory Markers ◽  
Metabolic Health ◽  
Late Gestation ◽  
Obese Mice ◽  
Rt Pcr ◽  
Metabolic Outcomes

Abstract Background and Aims: An alarming 40% of women of reproductive age have obesity and during pregnancy obesity adversely impacts metabolic health in mothers and offspring. Maternal complications include diabetes, preeclampsia and chronic kidney disease (CKD). Our previous work showed that offspring have increased risks of obesity, diabetes, and CKD. While pre-pregnancy weight optimisation is advocated, evidence of benefits for mother and offspring are lacking. We aimed to determine if weight loss prior to pregnancy, either with diet modification or liraglutide, improves maternal and offspring metabolic outcomes, and reduces kidney complications in obese mothers and the offspring. Methods: C57BL/6 female mice were fed a high-fat-diet (HFD) for 8 weeks and compared to lean chow-fed controls. HFD-fed dams were administered liraglutide (0.3mg/kg, s.c., for 4weeks) or switched to chow, to induce pre-conception weight loss. Pregnancy rates were observed after mating. Maternal anthropometry and glucose tolerance were measured before and after intervention, and at late gestation. Pregnant dams were either culled at gestational day 18–20 with blood and kidney harvested, or allowed to deliver their offspring. Offspring anthropometry, and glucose tolerance were assessed at postnatal week 12 after either HFD or chow feeding. Immunohistochemistry (IHC), western blotting and RT-PCR were used to measure kidney metabolic (FAS, SREBP) and inflammatory markers (CD-68,TGF-b). Results: HFD-fed dams had reduced glucose tolerance compared to chow-fed dams (p<0.0001), and higher expression of renal metabolic and inflammatory markers in late gestation (eg FAS <0.05, TGFb <0.05). Intervention with liraglutide or diet lowered body weight, improving glucose tolerance (both p<0.001), and fecundity. Markers of kidney damage, namely albuminuria and fibronectin (by RT-PCR and IHC) were reduced (both p<0.05). Liraglutide treated mice exhibited greater gestational weight gain than mice switched to chow (P<0.001). Markers of inflammation and oxidative stress were significantly lower in obese mice with preconception weight loss via diet compared to liraglutide (eg. MnSOD, PGC1α p<0.05). The offspring of obese mothers with pre-conception weight loss had lower body weight (p<0.001) and improved glucose tolerance (p<0.01). Kidney metabolic and inflammatory markers (MCP-1, FAS, SREBP, CD68) were significantly altered in HFD-fed offspring of obese mothers administered liraglutide pre pregnancy (p<0.05). Conclusions: Preconception weight loss improves fertility, weight and metabolic outcomes in mothers and the offspring, with benefits on reproduction, metabolic health, and chronic kidney disease risk. Therefore, obese women should be targeted for pre-conception weight loss to improve intergenerational metabolic health.

scholarly journals BACE1, but not BACE2, function is critical for metabolic disorders induced by high-fat diets in C57BL/6N mice

2021 ◽  
Author(s):  
Thomas W Rosahl ◽  
Lynn A Hyde ◽  
Patrick T Reilly ◽  
Marie-France Champy ◽  
Kristin J Belongie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
High Fat ◽  
Modest Improvement ◽  
Peripheral Tissues

Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta-cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimers disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. Bace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3 mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Our data indicate that lack of BACE1, but not BACE2, function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis.

scholarly journals The intravenous glucose tolerance and postprandial glucose tests may present different responses in the evaluation of obese dogs

2011 ◽  
Vol 106 (S1) ◽  
pp. S194-S197 ◽  
Author(s):  
Márcio Antonio Brunetto ◽  
Fabiano César Sá ◽  
Sandra Prudente Nogueira ◽  
Márcia de Oliveira Sampaio Gomes ◽  
Amanda Gullo Pinarel ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
Insulin Response ◽  
Obese Group ◽  
Control Group ◽  
Insulinogenic Index ◽  
Intravenous Glucose ◽  
Intravenous Glucose Tolerance

The present study compared the intravenous glucose tolerance test (IVGTT) and the glucose postprandial response (GPPR) test for the evaluation of glucose metabolism in obese dogs. A total of ten owned obese dogs (body condition score (BCS) of 9; fat mass, 45·7 (sem 1·51) %) were used. These dogs had their weight reduced by 20 % (BCS, 8; fat mass, 33·5 (sem 1·92) %; P < 0·001), designated as weight-reduced (WR) group. A control group of ten Beagle dogs was also included (BCS, 4·5; fat mass, 18·3 (sem 1·38) %; P < 0·01). Glucose tolerance was measured by two methods: IVGTT (infusion of 0·5 g of glucose/kg body weight) and GPPR (consumption of cooked rice to achieve 6 g of starch/kg body weight). When using the IVGTT, the area under the curve (AUC) for glucose and maximum glycaemia were higher for obese dogs compared with controls (P < 0·05), with intermediate results for the WR group (P>0·05). Basal insulin, insulin response peak, insulinogenic index and the AUC for insulin increment from 0 to 15 min and from 60 to 120 min were higher for the obese group (P < 0·05), while the WR group and control dogs showed similar results (P>0·05). When using the GPPR test, the AUC for insulin increment from 0 to 120 min was higher for the obese group compared with the control group (P < 0·05) and intermediate for the WR group (P>0·05). However, the AUC for insulin increment from 120 to 360 min was similar between the obese and WR groups (P>0·05), while it was lower for the control group (P < 0·05). The IVGTT showed that the loss of 20 % body weight resulted in an improvement of glucose control with reduced insulin secretion, and these same WR dogs showed higher insulin secretion with values similar to those of obese dogs when the GPPR test was used.

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

2007 ◽  
Vol 293 (1) ◽  
pp. E75-E82 ◽  
Author(s):  
M. J. De Blasio ◽  
M. Dodic ◽  
A. J. Jefferies ◽  
K. M. Moritz ◽  
E. M. Wintour ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Adult Male ◽  
Early Pregnancy ◽  
Male Offspring ◽  
Second Phase ◽  
Intravenous Glucose ◽  
Pregnant Sheep

An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life “programming”. Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, α-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.

scholarly journals Transgenerational metabolic outcomes associated with uteroplacental insufficiency

2013 ◽  
Vol 217 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Melanie Tran ◽  
Linda A Gallo ◽  
Andrew J Jefferies ◽  
Karen M Moritz ◽  
Mary E Wlodek
Keyword(s):  
Insulin Secretion ◽  
Birth Weight ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Insulin Response ◽  
Whole Body ◽  
Model Assessment ◽  
Β Cell ◽  
Pancreatic Morphology ◽  
First Phase Insulin Response

Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (−35%), which was associated with reduced pancreatic β-cell mass (−29%). By contrast, F2 restricted females had increased β-cell mass despite reduced first-phase insulin response (−38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.

scholarly journals Bisphenol A Exposure Disrupts Metabolic Health Across Multiple Generations in the Mouse

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2049-2058 ◽  
Author(s):  
Martha Susiarjo ◽  
Frances Xin ◽  
Amita Bansal ◽  
Martha Stefaniak ◽  
Changhong Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bisphenol A ◽  
Glucose Homeostasis ◽  
Early Life ◽  
Metabolic Health ◽  
Male Offspring ◽  
Differentially Methylated Region ◽  
Developmental Defects ◽  
Metabolic Phenotypes ◽  
Multiple Generations

Abstract Accumulating evidence has suggested that a suboptimal early life environment produces multigenerational developmental defects. A proposed mechanism is stable inheritance of DNA methylation. Here we show that maternal bisphenol A (BPA) exposure in C57BL/6 mice produces multigenerational metabolic phenotypes in their offspring. Using various methods including dual-energy X-ray absorptiometry analyses, glucose tolerance tests, and perifusion islet studies, we showed that exposure to 10 μg/kg/d and 10 mg/kg/d BPA in pregnant F0 mice was associated with higher body fat and perturbed glucose homeostasis in F1 and F2 male offspring but not female offspring. To provide insight into the mechanism of the multigenerational metabolic abnormalities, we investigated the maternal metabolic milieu and inheritance of DNA methylation across generations. We showed that maternal glucose homeostasis during pregnancy was altered in the F0 but not F1 female mice. The results suggested that a compromised maternal metabolic milieu may play a role in the health of the F1 offspring but cannot account for all of the observed multigenerational phenotypes. We further demonstrated that the metabolic phenotypes in the F1 and F2 BPA male offspring were linked to fetal overexpression of the imprinted Igf2 gene and increased DNA methylation at the Igf2 differentially methylated region 1. Studies in H19Δ3.8/+ mouse mutants supported the role of fetal Igf2 overexpression in altered adult glucose homeostasis. We conclude that early life BPA exposure at representative human exposure levels can perturb metabolic health across multiple generations in the mouse through stable inheritance of DNA methylation changes at the Igf2 locus.

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