||Ho, S-M, W-Y Tang, J Belmonte de Frausto, and GS Prins. 2006.
Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4. Cancer Research 66: 5624-5632.
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This laboratory study with rats provides the first evidence of a direct link between development of prostate cancer and early life exposure to two estrogenic chemicals, the natural human estrogen, estradiol, and bisphenol A (BPA), a synthetic molecule widely used in plastics and epoxy resins.
It suggests that exposure in the womb to estrogenic substances, like BPA, may alter gene behavior in a way that, later in life, leads to prostate cancer. In men, prostate cancer usually hits men over 50.
The doses of BPA used in the experiment were chosen to be within the exposure range experienced by many people.
Prostate cancer has increased steadily in men over the past several decades, coincident with increases in exposure to estrogenic substances like bisphenol A.
Other studies of BPA and prostate:
The scientists found that as the exposed rats aged, they were more likely than unexposed animals to develop a type of cancerous lesion in the prostate, prostatic intraepithelial neoplasia, or PIN, which is an early stage of prostate cancer in men.
The research also revealed that levels of the enzyme phosphodiesterase 4 rose during aging in exposed animals but not in unexposed. This enzyme breaks down cyclic AMP, a key signaling molecule that regulates cell growth and differentiation.
Other scientists had previously noted that phosphodiesterase 4 is higher in cancerous prostate cells than in normal prostate cells. As an animal ages normally, the gene that produces this enzyme, PDE4D4, becomes methylated and hence can no longer produce the enzyme.
Ho et al. discovered that in exposed animals the gene remains relatively unmethylated, so that it continues to produce phosphodiesterase. The scientists believe that PIN development may be a result of the altered methylation pattern, caused by BPA and estrogen exposure. With more phosphodiesterase than normal, there is less cyclic AMP, leading to abnormal cell growth and differentiation, and hence PIN formation.
What are PIN:
Prostatic Intraepithelial Neoplasia
PIN is a pattern of conditions that involve abnormal cell proliferation in particular locations within the prostate.
In people, PIN are generally agreed to be the precursor lesions of prostate cancer.
Medical specialists refer to low grade vs. high grade PIN. Low grade PIN is in early stages of development, or poorly developed. High grade PIN are taken much more seriously, as roughly one-third of men with high grade PIN develop prostate cancern within a year of detection.
While high grade PIN itself does not require treatment, many physicians commence treatment once detected because it is considered a harbinger of full-blown prostate cancer.
Their discovery of heightened phosphodiesterase levels is intriguing for an additional reason: They observed it before seeing overt signs of tissue damage. They believe it may provide an early warning for men on the path to prostate cancer.
What did they do? Ho et al. exposed neonatal male rats to different treatments and then observed their responses, as adults, to administration of elevated estradiol levels. As men age, they typically are exposed to more estrogens because of changes in body chemistry. All rats in the experiment received these hormone supplements in adulthood; the key comparison is between those that were treated differently in early development. The 4 dosing treatments (via subcutaneous injections in the neck, once each on days 1,3 and 5 after birth) were:
- One group (control) received only corn oil.
- Two estradiol treatments: a high dose group (HD-E), receiving 25 µg/pup (equivalent to 2,500 µg/kg body weight) and a low dose group (LD-E) receiving 0.001 µg/pup= 0.1 µg/kg body weight).
- One group received a low dose of BPA, receiving 0.1 µg/pup (or 10 µg/kg body weight).
- The low dose BPA (LD-BPA) treatment, equivalent to 10 parts per billion, was within the range of other low dose experiments, and chosen because it would produce levels comparable to those measured typically in people.
In adulthood, beginning 90 days after birth, each of the treatment groups above were split into two. Half of them received an implant that delivered estradiol and testosterone; the other half received an empty implant. The testosterone was necessary because the increase in estrogen has a negative effect on the animal's testosterone level and leads to prostate abnormalities without that supplement.
The implants remained in place for 16 weeks. The animals were sacrificed at 28 weeks of age (day 200 after birth). The
In addition to these animals, 5-7 individuals of each of the treatment groups had been sacrificed on days 10 and 90 after birth to allow DNA methylation analysis.
Ho et al. examined the prostates of sacrificed animals for indications of prostate abnormalites.
What did they find?
1. Developmental exposure to high dose estradiol (HD-E) decreased prostate weight but neither LD-E or LD-BPA affected prostate weight/size, for those animals that were not subsequently exposed in adulthood to elevated estradiol: This is consistent with previous research with this strain of rats.
2. For animals exposed in adulthood to elevated estradiol, prostate weight for each of the groups treated in early development did not change relative patterns compared to those not exposed in adulthood (above), with a decrease compared to controls for HD-E and no difference compared to controls for LD-E and LD-BPA.
3. This is the most important set of comparisons: In animals exposed to LD-BPA and adult hormone treatment, the PIN incidence increased from 40% (control) to 100%. Most were high-grade PIN. According to Ho et al., the PIN severity caused by BPA exposure was equivalent to that induced by HD-E. Animals exposed developmentally to LD-E, HD-E and LD-BPA all showed significant increases in PIN proliferation (below). Only HD-E showed elevated PIN scores without adult hormone treatment.
Animals that received LD-BPA followed by adult hormone treatment had greater PIN scores than controls with or without adult treatment and also than LD-BPA animals without adult treatment.
Groups on left did not receive adult hormone treatment whereas those on right did.
When they examined the animals prostate tissues for changes in epithelial cell proliferation, rates were low in control animals and in most of the treatments except: in areas where they observed high-grade PIN, they saw high rates of cell proliferation in the HD-E exposed animals (with or without treatment), and high rates in animals treated early with BPA and later in adulthood with hormones.
They saw a similar pattern when they looked at the distribution of apoptosis (below, right).
Black and red cross-hatched bars show relative amounts of apoptosis in histologically normal areas. These were low in all treatment groups.
In contrast, the rediped bars show the relative amount of apoptosis in areas with high-grade PIN. Apoptosis rates were high in HD-E regardless of adult treatment,and high in BPA-treated animals that recent hormone supplements in adulthood.
Ho et al. surveyed methylation patterns of a series of genes and compared differences among the treatment groups as animals aged. They found that treatment by estrogen and bisphenol A altered methylation patterns, many permanently, and that the differences were evident as early as day 10 after birth.
They then focused on one gene in particular, PDE4D4, which controls production of the enzyme phosphodiesterase 4. This enzyme breaks down cyclic AMP, a signaling molecule that regulates cell growth and differentiation.
They found that as normal animals age, specific regions of the PDE4D4 gene become hypermethylated, leading to a reduction in the production of phosphodiesterase 4.
Animals exposed neonatally to LD-E, HD-E and LD-BPA all failed to follow this pattern: In them, the same regions of the PDE4D4 gene remain relatively unmethylated. Ho et al. showed, as expected given these differences in methylation, that phosphodiesterase levels in control animals dropped as they aged. In contrast, in those exposed to E and BPA circulating levels of phosphodiesterease 4 continue to increase with age.
What does it mean? This paper presents two important insights into the possible causes of prostate cancer. First, it establishes the first link between early developmental exposure to bisphenol A and estradiol, and formation of high-grade PIN, prostate abnormalities generally accepted to be precursors of prostate cancer in humans. The BPA dose used in this experiment was chosen to be within the range of common human exposure.
Second, it reveals a potential molecular mechanism by which PIN formation may be caused: developmental exposure to E and BPA prevents increasing methylation of PDE4D4, which normally occurs as animals age. Ho et al. propose that the reduced methylation in exposed animals may adversely affect cell signaling and thereby cause normal tissues to become cancerous.
The changes in PDE4D4 expression were evident early in development, long before prostatic lesions could be detected, raising the possibility that measurements of phosphodiesterase levels could identify individuals at risk to prostate cancer.
This study adds significantly to the weight of evidence that developmental exposure to endocrine disrupting contaminants can cause adverse effects in adulthood.