Evidence continues to mount about the harmful effects of bisphenol A (BPA), a common chemical used in some dental sealants and a number of consumer and household products.
The Endocrine Society’s annual meeting in San Francisco last week included two studies linking BPA to harmful effects on male fetuses and prostate cancer. One study found an association between BPA exposure and defects in a testicular hormone in newborn boys with undescended testicles, the most frequent congenital malformation in male newborns. The second showed that exposing developing tissue to low levels of BPA is associated with a greater incidence of prostate cancer in tissue grown from human prostate stem cells.
A third study found that fetal exposure to BPA could lead to increased inflammation in fat tissues after birth, which can lead to obesity and metabolic syndrome.
Undescended testicles
For the first study, researchers from University Hospital of Nice in France studied 180 boys born after 34 weeks gestation between 2003 and 2005. Fifty-two were born with one or two undescended testicles, 26 of whom still had the condition at 3 months of age. The other 128 newborns did not have this birth defect and were matched for pregnancy term, weight, and time of birth (the control group).
Using sensitive immunoassays of the infants’ umbilical cord blood, the researchers measured the newborns’ levels of BPA and insulin-like peptide 3, one of the two testicular hormones that regulate descent of the testicles.
Testosterone level, which also controls fetal testicular descent, did not differ between the groups and was normal in the whole population, according to Patrick Fenichel, MD, PhD, a professor and the head of reproductive endocrinology at University Hospital. The infants with cryptorchidism had significantly lower levels of insulin-like peptide 3, compared with the controls. These infants did not have greatly increased levels of BPA or several other environmental endocrine disrupters that were measured. However, in all 180 infants, the BPA level inversely correlated with the level of insulin-like peptide 3, meaning that the higher the BPA level, the lower the level of this important testicular hormone.
While this study by itself cannot be considered as definitive evidence for an environmental cause of undescended testis, Dr. Fenichel noted, it suggests for the first time in humans a link that could contribute to one cofactor of idiopathic undescended testes.
Prostate cancer risk
In the second study, investigators from the University of Illinois at Chicago used human prostate stem cells from organ donors to grow prostate tissue in a mouse model.
Lead author Gail Prins, PhD, a professor of physiology and urology at the university, and her colleagues 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 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, they 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.
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% of non-BPA exposed tissue and 33% to 45% of tissue exposed to BPA.
"The main takeaway from this study is that we have seen, for the first time using our innovative model system (human prostate tissue implanted into a mouse "host"), that human prostate stem cells, if exposed to BPA in early development, will produce prostate tissue that is much more susceptible to developing prostate cancer years down the road in adulthood," Dr. Prins explained in an email to DrBicuspid.com.
The results suggest that stem cells are direct BPA targets, which may explain the long-lasting effects of this chemical throughout the body, according to Dr. Prins. "The Prins lab discovered that these early stem and progenitor cells in the prostate have estrogen receptors and are stimulated to divide when given either estradiol or BPA," she noted. "Further, in the stem cells, the BPA acted to ‘sensitize’ these cells to the effects of estrogen later, when the cells differentiated to other prostate cell types." Estrogen rises naturally in men and fuels prostate cancer; consequently, greater sensitivity to it could lead to higher chances of getting prostate cancer.
This is the first direct in vivo evidence that developmental exposure to environmentally relevant levels of BPA increases human prostate cancer risk, Dr. Prins noted.
Dr. Prins and her team will continue to research BPA’s effect on stem cells. "We’ll look at how BPA changes the genetic expression of these stem cells through epigenetic changes," she stated. “Our data thus far indicate that BPA alters the noncoding RNAs in the prostate stem cells and our future studies will focus on how this can predispose to cancer."
Inflamed tissue and obesity
Prior research has linked BPA in both animals and humans to obesity and the metabolic syndrome, which is a cluster of metabolic risk factors that increase the chance of later developing diabetes, heart disease, and stroke. However, the study led by Almudena Veiga-Lopez, DVM, PhD, a research investigator at the University of Michigan, is the first to show that prenatal BPA exposure increases postnatal fat tissue inflammation, a condition that underlies the onset of metabolic diseases.
The researchers examined the effects of BPA on sheep and improved the understanding of how prenatal BPA exposure regulates the inflammatory response in offspring in the tissues that are relevant to development of metabolic disease. Sheep have similar body fat to that in humans, including visceral (deep belly) fat and subcutaneous fat just below the surface of the skin, according to Veiga-Lopez.
The researchers fed two groups of pregnant sheep corn oil with or without added BPA at a dose needed to achieve BPA levels similar to those seen in human cord blood in the umbilical cord blood of the sheep offspring. Of the female offspring from the sheep, half from each group were overfed at approximately 6 weeks of age. All female offspring then were divided into four groups of nine to 12 animals each: non-BPA-exposed controls that received a normal diet; BPA-exposed offspring that received a normal diet; overfed, obese controls; and overfed, obese, BPA-exposed offspring.
At 15 months of age, sheep underwent a glucose tolerance test, to measure their insulin and blood sugar levels. Seven months later, the researchers collected samples of the animals’ visceral and subcutaneous fat tissues to evaluate levels of two biological markers of inflammation. These biomarkers were CD68, a marker for inflammatory cells, and adiponectin, a molecule with a known role in the development of metabolic syndrome. When the adiponectin level decreases or CD68 expression increases, inflammation is worse, Veiga-Lopez noted.
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