Dataset Information

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

ABSTRACT: Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation in wildtype offspring of the C57Bl/6J mouse strain. While offspring fed a HF/HS post-weaning diet resulted in poor metabolic health and decreased uterine weight (regardless of maternal diet), it did not lead to ECa. We also investigated the effects of the maternal obesogenic diet on ECa development in a Diethylstilbestrol (DES) carcinogenesis mouse model. All mice injected with DES had reproductive tract lesions including decreased number of glands, condensed and hyalinized endometrial stroma, and fibrosis and increased collagen deposition that in some mice extended into the myometrium resulting in extensive disruption and loss of the inner and outer muscular layers. Fifty percent of DES mice that were exposed to maternal HF/HS diet developed several features indicative of the initial stages of carcinogenesis including focal glandular and atypical endometrial hyperplasia versus 0% of their Chow counterparts. There was an increase in phospho-Akt expression in DES mice exposed to maternal HF/HS diet, a regulator of persistent proliferation in the endometrium, and no difference in total Akt, phospho-PTEN and total PTEN expression. In summary, maternal HF/HS diet exposure induces endometrial hyperplasia and other precancerous phenotypes in mice treated with DES. This study suggests that maternal obesity alone is not sufficient for the development of ECa, but has an additive effect in the presence of a secondary insult such as DES.

SUBMITTER: Owuor TO

PROVIDER: S-EPMC5959064 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

Owuor Theresa O TO Reid Michaela M Reschke Lauren L Hagemann Ian I Greco Suellen S Modi Zeel Z Moley Kelle H KH

PloS one 20180518 5

Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation ...[more]

PMID: 29775456

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Project description:Obesity affects oocyte mitochondrial functions and reduces oocyte quality and fertility. Obesity may also increase the risk of metabolic disorders in the offspring. Children are likely to follow their parents lifestyle and diet, which also contributes to the increased prevelance of obesity across generations. We hypothesise that the impact of obesogenic (OB) diet and obesity on oocyte mitochondrial functions is different in offspring born to obese mothers compared to those born to healthy mothers. To test this hypothesis, we fed a control (C, 10% fat, 7% sugar) or an OB diet (60% fat, 20% sugar) to female mice (for 7 weeks (w)) and then to their female offspring (for 7w after weaning) in a 2 × 2 factorial design (C » C, n = 35, C » OB, n = 35, OB » C n = 49 and OB » OB, n = 50). Unlike many other studies, we used an outbred Swiss mouse model to increase the human pathophysiological relevance. Offspring were sacrificed at 10w and their oocytes were collected. Offspring OB diet increased oocyte lipid droplet content, mitochondrial activity and reactive oxygen species (ROS) levels, altered mitochondrial ultrastructure and reduced oocyte pyruvate consumption. Mitochondrial DNA copy numbers and lactate production remained unaffected. Mitochondrial ultrastructure was the only factor where a significant interaction between maternal and offspring diet effect was detected. The maternal OB background resulted in a small but significant increase in offspring's oocyte mitochondrial ultrastructural abnormalities without altering mitochondrial inner membrane potential, active mitochondrial distribution, mitochondrial DNA copy numbers, or ROS production. This was associated with reduced mitochondrial complex III and V expression and reduced pyruvate consumption which may be compensatory mechanisms to control mitochondrial inner membrane potential and ROS levels. Therefore, in this Swiss outbred model, while offspring OB diet had the largest functional impact on oocyte mitochondrial features, the mitochondrial changes due to the maternal background appear to be adaptive and compensatory rather than dysfunctional.

Project description:The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia in vivo and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment in vitro, hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our in vivo study showed that while endometrial ER? expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ER? and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ER? expression without affecting ER? expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ER?-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.

Dataset Information

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

Publications

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

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