It has recently been confirmed that endocrine-disrupting chemicals, which are considered harmless individually and in small doses, can have detrimental effects on male fertility when combined.
A large number of young males have a reduced sperm count (oligozoospermia) and an increasing number are being born with deformities of their sexual organs. Such deformities include hypospadias, where the urethral opening is on the underside of the penis, and in Denmark have a prevalence of almost 5%. Substances that disturb the hormonal balance during fetal development are suspected of playing a part in these birth defects.
It has already been shown through animal tests that endocrine-disrupting chemicals, which have an effect on the male hormone testosterone, can result in similar malformations in rats. Both in vitro testing and short-term animal testing have revealed that despite the fact that when exposed to each substance individually, no detrimental effect is observed, concurrent exposure to several chemical substances can result in endocrine-disrupting effects.
A group led by Ulla Hass, a senior scientist at the National Food Institute, Technical University of Denmark, (Lyngby, Denmark) has carried out studies in which pregnant rats were exposed to a cocktail consisting of three chemicals (the drug flutamide and the pesticides vinclozolin and procymidone) resulting in testosterone inhibition. All three chemicals were administered in doses that are harmless individually, although it was shown that extended exposure to the cocktail did have significant effects. These included the development of female characteristics, such as retained nipples, and the severe malformation of external genitalia. For example, 60% of the male rats were born with hypospadia.
Sofie Christiansen, a PhD student at the National Food Institute, Technical University of Denmark stated that, “Studies [have shown] that concurrent exposure to several endocrine-disrupting substances in small doses can increase the frequency of malformations, such as hypospadias, even though the doses are harmless individually. It is therefore, not sufficient to establish reference values only by looking at one substance at a time”.
It can therefore be concluded that, in order for a proper assessment of the potentially harmful effects of these chemicals to be carried out, it is essential to include the possible concurrent exposure of two or more chemicals in the risk assessment. Ulla Hass concluded “To establish an adequate protection level for consumers, potential cocktail effects should be taken into account, and thus the way a chemical may interact with other chemicals.”
Christiansen S, Scholze M, Axelstad M, Boberg J, Kortenkamp A, Hass U. Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat. Int. J. Androl. 31(2), 241–248 (2008).
Harmful effects of synthetic estrogens on the female reproductive system
Synthetic estrogens, such as synthetic estrogen diethylstilbestrol (DES), found in many widely used plastics, have been shown in the past to have harmful effects on the developing fetus, resulting in fertility problems and, in extreme cases, vaginal and breast cancer. DES alters homeobox A10 (HOXA10) expression, a gene essential for uterine development, resulting in an increase in the risk of cancer and pregnancy complications in female offspring.
A study led by Hugh Taylor at the Department of Obstetrics, Gynecology and Reproductive Medicine at the Yale School of Medicine (CT, USA) investigated the cause behind the development of uterine cancer years after fetal exposure to DES.
The offspring of 30 pregnant mice were injected with DES and their DNA was analyzed. Alterations to certain regions of the HOXA10 gene were observed, and these persisted into adulthood, indicating that such changes are permanent. “HOXA10 protein expression was shifted to the bottom portion of the uterus in the female offspring. [They] also found increased amounts of the enzyme responsible for changes in the DNA. Rather than just changing how much protein is there, DES is actually changing the structure of the HOXA10 gene” commented Hugh Taylor.
Although products containing DES are no longer available on the market, similar substances with estrogen-like properties, such as Bisphenol-A, found in common household plastics and known to impact on fertility, may still pose a threat to pregnant women.
Taylor HS, Bromer J, Wu J. Preliminary results of the study will be presented at the Society for Gynecologic Investigation 55th Annual Scientific Meeting, San Diego, CA 26–29 March (2008).
Signaling molecule implicated in breast cancer metastasis
TGF-β is a cytokine that normally functions as a tumor suppressor. However, a recent study led by researchers at the Memorial Sloan–Kettering Cancer Center (NY, USA) revealed that cancer cells in humans are able to misuse cytokines, such as TGF-β, to their advantage, by inducing them to enhance a tumor’s ability to metastasize rather than suppressing it. Metastasis is the cause of approximately 90% of all cancer-related deaths.
Computer-based analysis was carried out on a cohort of patient tumor samples in order to classify them according to their levels of TGF-β. It was observed that approximately half of all the breast tumors analyzed contained active TGF-β. Such tumors were also found to be more aggressive and more likely to metastasize to the lung. The researchers discovered that TGF-β induces breast cancer cells to produce angiopoietin-like 4 (ANGPTL4), a second cytokine, via the Smad signaling pathway. ANGPTL4 derived from tumor cells disrupts vascular endothelial cell–cell junctions, increases the permeability of lung capillaries, and facilitates passage of tumor cells to the lungs. Joan Massague, who has led the study, stated that “TGF-β enhances human breast cancer metastasis [and their study] reveals how tumor cells learn to exploit cytokines by making them work as a relay system to promote the spread of breast cancer”.
Work is continuing to assess whether or not TGF-β and ANGPTL4 may also be active in other tumor types, with the aim of establishing ways in which to interfere with the action of these cytokines in order to prevent metastasis. David Padua, the study’s lead author added: ‘Deciphering how cancer cells take advantage of these cytokines is essential for developing therapies that can prevent this process. Because cytokines can act outside of cells they can be more easily targeted by drugs that block their activity”.
This study has revealed that ANGPTL4 is a potential target for the disruption of TGF-β-induced metastasis, and TGF-β-blocking compounds are already at the clinical trial stage as drug candidates for cancer types. such as breast and melanoma.
Padua D, Zhang XH, Wang Q et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1), 66–77 (2008).
A step closer to producing an effective male contraceptive pill
A new study has revealed that hormonal contraception may potentially become a safe, effective and reversible form of birth control. It has been shown that sperm production is suppressed more quickly by the combination of testosterone and progestin, rather than testosterone alone.
Peter Y Liu of the University of Sydney, Australia led the study and said that “it is possible to suppress sperm output to concentrations that are comparable with reliable contraception in most, but not all men [and] the rate of suppression is comparable to that achieved after a vasectomy”.
In this study, all published male hormonal contraceptive studies carried out between 1990 and 2006 where treatment duration lasted for a minimum of 3 months were analyzed. Out of a total of 30 studies, 1756 men between the ages of 18 and 51 years were treated with different preparations of testosterone, either including or excluding various preparations of the progestin hormone (a synthetic progesterone, also used in combination with estrogen for female contraception). It was concluded from the analysis that the combination of testosterone and progestin was more effective at suppressing sperm production than testosterone alone. Liu stated that this combination “May make long-term hormonal contraception safer by reducing the dose of testosterone needed for maintenance contraception”.
Discrepancies were observed in the speed of suppression of sperm output between Caucasian and non-Caucasian males. Furthermore, younger males with naturally lower testosterone levels had a slightly faster sperm suppression, although the differences were almost negligible. The findings of this investigation also revealed that the prediction of which men will be the most responsive to the treatment, suppressing sperm output to levels consistent with reliable male contraception, remains complex. “Considerable progress has been made toward finding an effective combination of these hormones [although] the current analysis did not take into account the different types of progestins” said Liu. This is something that will have to be taken into consideration in successive studies, and therefore, more research is required before the optimum combination of hormones is unveiled.
Liu PY, Swerdloff RS, Bradley DA et al. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J. Clin. Endocrinol. Metab. (2008) (Epub ahead of print).
Stem cell research offers new hope for Type 1 diabetes cure
In the quest for finding new treatments and eventually a cure for diabetes, scientists have succeeded in establishing a new technique that can turn embryonic stem cells into insulin-producing pancreatic tissue.
Pluripotent stem cells can give rise to any fetal or adult cell type, and scientists believe that this property may be the key to treating a number of diseases, including Alzheimer’s, Parkinson’s and diabetes. A major difficulty faced by scientists in the development of such treatments is in ensuring that the stem cells differentiate into the desired cell type. The majority of these cells differentiate into simple nerve cells called neurons, with fewer than 1% becoming insulin-producing pancreatic cells. The challenge, therein, lies in finding a way to induce the production of greater quantities of these cells.
A team of scientists at the University of Manchester (UK), in collaboration with a team at the University of Sheffield (UK), have been able to genetically manipulate embryonic stem cells to produce the transcription factor PAX4, which induces as much as 20% of embryonic stem cells to differentiate into pancreatic β-cells. These cells have the potential to produce insulin when transplanted into the body. Furthermore, scientists were able to separate the new β-cells from other types of cells produced using fluorescent-activated cell sorting, which is a specialized type of flow cytometry, enabling the sorting of a heterogeneous mixture of biological cells into two or more containers, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell.
Karen Cosgrove, who led the team in Manchester’s Faculty of Life Sciences, stated that “Research in the United States has shown that transplanting a mixture of differentiated cells and stem cells can cause cancer, so the ability to isolate the pancreatic cells in the lab is a major boost in [their] bid to develop a successful therapy”. Scientists have already been successful in increasing the number of pancreatic cells produced by altering the environment in which stem cells develop. Therefore, combining the two techniques will potentially provide the proportions of pancreatic cells required, while eliminating the contamination from other cell types.
Scientists believe that the transplantation of functional β-cells into the liver (as this organ has a strong blood supply) offers the best hope of finding a cure for Type 1 diabetes and potentially even Type 2.
The pancreatic cells produced by the team in Manchester resembled fetal pancreatic cells rather than adult tissue, although tests carried out on mice have revealed that these cells are able to develop into adult cells following transplantation. Although potential cures for diabetes are the ultimate goal, the most exciting and immediate outcome of this research is that a supply of human pancreatic cells can now be provided for the elucidation of the disease process of diabetes, together with providing a source on which to test novel drugs.
Liew CG, Shah NN, Briston SJ et al. PAX4 enhances β-cell differentiation of human embryonic stem cells. PLoS ONE 3(3), e1783 (2008).