June 17, 2013 Exposing developing tissue to low levels of the plastic bisphenol A, commonly known as BPA, is linked to a greater incidence of prostate cancer in tissue grown from human prostate stem cells, a new study finds. The results were presented Monday, June 17, at The Endocrine Society's 95th Annual Meeting in San Francisco.

BPA is a synthetic estrogen that is used to add flexibility to many common products, including food cans and containers, compact discs, eyeglasses, and even baby bottles. It is universally prevalent, and tests indicate that almost everyone has measurable levels of the chemical in their bodies.

The chemical has received a great deal of media attention in recent years because of its potential to increase the risk of disease. The concern about BPA in the human body is that it is an endocrine-disrupting chemical, which means that it alters the body's hormonal balance by replicating the activity of a naturally occurring hormone. In this case, BPA replicates the activity of estrogen. Of greatest concern are BPA's effects on developing fetuses and infants because endocrine-disrupting chemicals are thought to predispose developing cells to later disease.

In this study, investigators used human prostate stem cells from organ donors to grow prostate tissue in a mouse model. They found that early BPA exposure significantly increased the risk of both prostate cancer and a precancerous condition known as prostate epithelial neoplasia, or PIN. The incidence rates for PIN and prostate cancer were:

12 percent of non-BPA exposed tissue

33-45 percent of tissue exposed to BPA

"These results suggest that stem cells are direct BPA targets which may explain the long-lasting effects of this chemical throughout the body," said study lead author Gail S. Prins, Ph.D., professor of physiology and urology at the University of Illinois at Chicago. "They provide the first direct in vivo evidence that developmental exposure to environmentally relevant levels of BPA increases human prostate cancer risk."

Investigators were able to observe the effects of BPA on living prostate tissue by isolating prostate stem cells from young men, then combining these cells with undifferentiated cells called mesenchyme, which, for this study, derived from rat tissue. They then grafted this combined tissue to the kidneys of mice where the tissue developed into human prostate tissue. To simulate human BPA exposure, the investigators fed BPA at levels found in humans to the study mice for the first two weeks of the prostate-tissue formation.

One month after the tissue graft, when the prostate tissue had matured, the investigators administered estrogen and testosterone at elevated levels to the study mice to promote prostate disease.

The National Institutes of Health's National Institute of Environmental Health Sciences funded the study.

See original here:
Exposure to low doses of BPA linked to increased risk of prostate cancer in human stem cells

Public release date: 17-Jun-2013 [ | E-mail | Share ]

Contact: David McKeon dmckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation

NEW YORK, NY (June 17, 2013) A team from the New York Stem Cell Foundation (NYSCF) Research Institute and the Naomi Berrie Diabetes Center of Columbia University has generated patient-specific beta cells, or insulin-producing cells, that accurately reflect the features of maturity-onset diabetes of the young (MODY).

The researchers used skin cells of MODY patients to produce induced pluripotent stem (iPS) cells, from which they then made beta cells. Transplanted into a mouse, the stem cell-derived beta cells secreted insulin in a manner similar to that of the beta cells of MODY patients. Repair of the gene mutation restored insulin secretion to levels seen in cells obtained from healthy subjects. The findings were reported today in the Journal of Clinical Investigation.

Previous studies have demonstrated the ability of human embryonic stem cells and iPS cells to become beta cells that secrete insulin in response to glucose or other molecules. But the question remained as to whether stem cell-derived beta cells could accurately model genetic forms of diabetes and be used to develop and test potential therapies.

"We focused on MODY, a form of diabetes that affects approximately one in 10,000 people. While patients and other models have yielded important clinical insights into this disease, we were particularly interested in its molecular aspectshow specific genes can affect responses to glucose by the beta cell," said co-senior author Dieter Egli, PhD, Senior Research Fellow at NYSCF, who was named a NYSCFRobertson Stem Cell Investigator in 2012.

MODY is a genetically inherited form of diabetes. The most common form of MODY, type 2, results in a loss-of-function mutation in one copy of the gene that codes for the sugar-processing enzyme glucokinase (GCK). With type 2 MODY, higher glucose levels are required for GCK to metabolize glucose, leading to chronic, mildly elevated blood sugar levels and increased risk of vascular complications.

MODY patients are frequently misdiagnosed with type 1 or 2 diabetes. Proper diagnosis can not only change the patient's course of treatment but affect family members, who were previously unaware that they, too, might have this genetic disorder.

NYSCF scientists took skin cells from two Berrie Center type 2 MODY patients and "reprogrammed"or revertedthem to an embryonic-like state to become iPS cells. To examine the effect of the GCK genetic mutation, they also created two genetically manipulated iPS cell lines for comparison: one fully functional (two correct copies of the GCK gene) and one with complete loss of function (two faulty copies of the GCK gene). They then generated beta cell precursors from the fully functional and loss-of-function iPS cell lines and transplanted the cells for further maturation into immune-compromised mice.

"Our ability to create insulin-producing cells from skin cells, and then to manipulate the GCK gene in these cells using recently developed molecular methods, made it possible to definitively test several critical aspects of the utility of stem cells for the study of human disease," said Haiqing Hua, PhD, lead author on the paper, a postdoctoral fellow in the Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center at Columbia University and the New York Stem Cell Foundation Research Institute.

Follow this link:
NYSCF and Columbia researchers demonstrate use of stem cells to analyze causes, treatment of diabetes

NYSCF AND COLUMBIA RESEARCHERS DEMONSTRATE USE OF STEM CELLS TO ANALYZE CAUSES AND TREATMENT OF DIABETES

Using patient-specific stem cells to correct deficient insulin-producing cells

Newswise NEW YORK, NY (June 17, 2013) A team from the New York Stem Cell Foundation (NYSCF) Research Institute and the Naomi Berrie Diabetes Center of Columbia University has generated patient-specific beta cells, or insulin-producing cells, that accurately reflect the features of maturity-onset diabetes of the young (MODY).

The researchers used skin cells of MODY patients to produce induced pluripotent stem (iPS) cells, from which they then made beta cells. Transplanted into a mouse, the stem cell-derived beta cells secreted insulin in a manner similar to that of the beta cells of MODY patients. Repair of the gene mutation restored insulin secretion to levels seen in cells obtained from healthy subjects. The findings were reported today in the Journal of Clinical Investigation.

Previous studies have demonstrated the ability of human embryonic stem cells and iPS cells to become beta cells that secrete insulin in response to glucose or other molecules. But the question remained as to whether stem cell-derived beta cells could accurately model genetic forms of diabetes and be used to develop and test potential therapies.

We focused on MODY, a form of diabetes that affects approximately one in 10,000 people. While patients and other models have yielded important clinical insights into this disease, we were particularly interested in its molecular aspectshow specific genes can affect responses to glucose by the beta cell, said co-senior author Dieter Egli, PhD, Senior Research Fellow at NYSCF, who was named a NYSCFRobertson Stem Cell Investigator in 2012.

MODY is a genetically inherited form of diabetes. The most common form of MODY, type 2, results in a loss-of-function mutation in one copy of the gene that codes for the sugar-processing enzyme glucokinase (GCK). With type 2 MODY, higher glucose levels are required for GCK to metabolize glucose, leading to chronic, mildly elevated blood sugar levels and increased risk of vascular complications.

MODY patients are frequently misdiagnosed with type 1 or 2 diabetes. Proper diagnosis can not only change the patients course of treatment but affect family members, who were previously unaware that they, too, might have this genetic disorder.

NYSCF scientists took skin cells from two Berrie Center type 2 MODY patients and reprogrammedor revertedthem to an embryonic-like state to become iPS cells. To examine the effect of the GCK genetic mutation, they also created two genetically manipulated iPS cell lines for comparison: one fully functional (two correct copies of the GCK gene) and one with complete loss of function (two faulty copies of the GCK gene). They then generated beta cell precursors from the fully functional and loss-of-function iPS cell lines and transplanted the cells for further maturation into immune-compromised mice.

Our ability to create insulin-producing cells from skin cells, and then to manipulate the GCK gene in these cells using recently developed molecular methods, made it possible to definitively test several critical aspects of the utility of stem cells for the study of human disease, said Haiqing Hua, PhD, lead author on the paper, a postdoctoral fellow in the Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center at Columbia University and the New York Stem Cell Foundation Research Institute.

Read more:
Researchers Demonstrate Use of Stem Cells to Analyze Causes and Treatment of Diabetes