Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights

Association between fetal DES-exposure and psychiatric disorders ; another DES tragedy?

image of depression
The researchers identified ten relevant studies reporting the psychiatric outcome of offspring with a history of in utero DES exposure compared to a control group. Depression by Karina Lamontagne.

2012 Study Abstract

OBJECTIVES:
We explored whether in utero Diethylstilbestrol (DES) exposure has produced consistent findings with regard to an increased risk of psychiatric disorders.

METHODS:
We reviewed systematically the epidemiological studies investigating a possible association between prenatal DES exposure and risk of psychiatric disorders.

RESULTS:
We identified 10 relevant studies reporting the psychiatric outcome of offspring with a history of in utero DES exposure compared to a control group. We classified them into four categories:

  1. a mail survey in a sample from a randomized double-blind controlled trial of prophylactic DES for first pregnancy in the early 1950s reported that depression and anxiety were twice as frequent in the exposed group compared to the placebo group;
  2. five small clinical samples with inconclusive results;
  3. two large cohorts of DES-exposed participants:
    1. the first study reported a higher lifetime history of weight loss related to anorexia nervosa
    2. whereas the second did not found any significant difference;
  4. two subsamples from general population cohorts:
    1. the first study did not found any significant difference
    2. whereas the second reported that exposed women showed a higher rate of incident depression than non-exposed women.

CONCLUSIONS:
The role of prenatal exposure to DES as an environmental risk factor for psychiatric disorders requires more evidence before any conclusions can be drawn. If confirmed, several explanations could be proposed: gene × environment interaction and epigenetic mechanisms, although phenocopy and gene-environment aggregation are plausible.

Sources and more information
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Les perturbateurs endocriniens et la puberté précoce

Environnement et précocité pubertaire chez la fille

Intervention du Pr Charles Sultan, endocrinologue au CHU de Montpellier sur les perturbateurs endocriniens et la puberté précoce, lors de la table-ronde “Perturbateurs endocriniens : effets et mécanismes d’action de la conception à la maturité” organisée par WECF le 10 avril 2012 à l’Assemblée nationale.

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Periconceptional and early fetal exposures to Endocrine Disruptors

EDCs: effects and mechanisms of action from conception to maturity

Dr Shanna H. Swan, Vice-Chair of the Department of Research of Preventive Medicine, Mount Sinai School of Medecine (USA) presentation on “Periconceptional and early fetal exposures to Endocrine Disruptors (EDCs)” during the roundtable on “EDCs: Effects and mechanisms of action from conception to maturity” on April 10th, 2012 organised by Women in Europe for a Common Future.

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The Rise of Superbugs Resistant to Antibiotics

How the deadly misuse of antibiotics is threatening our world

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Synthèse résultats enquête Loi Bertrand 2012

Présentation diaporama de Market iT sur SlideShare

Sommaire

  • Enquête Loi Bertrand Présentation
  • Principaux résultats et profil des participants et participation
  • Impacts sur la relation Professionnels de Santé – Entreprises
  • L’avis des Professionnels de Santé
  • En synthèse… pour ou contre cette loi de transparence?
  • L’avis des collaborateurs des entreprises concernées
  • Les difficultés rencontrées dans leur projet Loi Bertrand
Sources:

Differential Effects of BPA and DES on Human, Rat and Mouse Fetal Leydig Cell Function

EDCs have been incriminated in the current increase of male reproductive alterations

mouse-lab-rat image
This 2012 study shows for the first time that concentrations of BPA as low as 10−8 M are sufficient to reduce fetal testis endocrine activity in humans.

2012 Study Abstract

Endocrine disruptors (ED) have been incriminated in the current increase of male reproductive alterations. Bisphenol A  (BPA) is a widely used weak estrogenic environmental ED and it is debated whether BPA concentrations within the average internal exposure are toxic. In the present study we investigated the effects of 10−12 to 10−5 M BPA concentrations on fetal Leydig cell function, as fetal life is a critical period of sensitivity to ED effects on male reproductive function. To this aim, fetal testes from human at 6.5–10.5 gestational weeks (GW) or from rat and mouse at a comparable critical period of development (14.5 days post-coitum (dpc) for rat and 12.5 dpc for mouse) were explanted and cultured using our validated organotypic culture system in the presence or absence of BPA for 1–3 days. BPA concentrations as low as 10−8 M reduced testosterone secretion by human testes from day 1 of culture onwards, but not by mouse and rat testes where concentrations equal to 10−5 M BPA were required. Similarly, 10−8 M BPA reduced INSL3 mRNA levels only in human cultured testes. On the contrary, 10−5 and 10−6 M diethylstilbestrol (DES), a classical estrogenic compound, affected testosterone secretion only in rat and mouse testis cultures, but not in human testis cultures. Lastly, contrarily to the DES effect, the negative effect of BPA on testosterone produced by the mouse fetal testis was maintained after invalidation of estrogen receptor α (ERα). In conclusion, these results evidenced i) a deleterious effect of BPA on fetal Leydig cells function in human for concentrations from 10−8 M upwards, ii) species-specific differences raising concerns about extrapolation of data from rodent studies to human risk assessment, iii) a specific signaling pathway for BPA which differs from the DES one and which does not involve ERα.

2012 Study Conclusions

We show here for the first time that concentrations of BPA as low as 10−8 M are sufficient to reduce fetal testis endocrine activity in humans. The mechanism of action of BPA will need further investigation, but it is likely to involve non-classical estrogen receptors.

The negative effect of BPA on testosterone production and Insl 3 expression during fetal life observed here during the “masculinization programming window”, may have several consequences as it can impair the masculinization of internal and external genitalia [4], [7], [13]. Our present results should encourage prospective epidemiological studies to investigate the possible association between environmental exposure to BPA during pregnancy and anogenital distance at birth. Furthermore, BPA-induced reduction of fetal testosterone production may have long-term consequences. Although brain masculinization and the onset of male-specific sexual behaviors start during the second half of pregnancy, we can’t exclude that BPA-induced reduction of fetal testosterone production during the first trimester of pregnancy may influence these parameters [70]. It may also affect the germ cell lineage since androgens control gonocyte development [71]. Thus, it will be relevant to study the effect of BPA on gonocytes since alterations of the germ cell lineage may result in testicular cancer or in reduced sperm production [3], [4] and may also explain the recently reported multigenerational effects of BPA [72].

Finally, our findings challenge the widespread use of rodent models to assess the toxic effects of EDs and highlight the need for setting up specific tools to study reprotoxicity in humans.

Sources and Full Study
  • Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function, PLOS one, DOI: 10.1371/journal.pone.0051579, December 17, 2012.
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Effect of in utero exposure to DES on lumbar and femoral bone, articular cartilage, intervertebral disc

DES significantly affected the musculoskeletal system of adult mice

lab-mouse image
DES significantly affected the musculoskeletal system of adult mice. Results suggest that environmental estrogen contaminants can have a detrimental effect on the developmental lumbar bone growth and mineralization in mice. Further studies measuring the impact of environmental estrogen mimics, such as bisphenol A, are then warranted.

2012 Study Abstract

INTRODUCTION:
Developmental exposure to estrogens has been shown to affect the musculoskeletal system. Furthermore, recent studies have shown that environmental exposure to estrogen-like compounds is much higher than originally anticipated. The aim of this study was to determine the effects of diethylstilbestrol (DES), a well-known estrogen agonist, on articular cartilage, intervertebral disc (IVD), and bone phenotype.

METHODS:
C57Bl/6 pregnant mice were dosed orally with vehicle (peanut oil) or 0.1, 1.0, and 10 μg/kg/day of DES on gestational days 11 to 14. Male and female pups were allowed to mature without further treatment until 3 months of age, when swim and sedentary groups were formed. After euthanasia, bone mineral density (BMD), bone mineral content (BMC), bone area (BA), and trabecular bone area (TBA) of the lumbar vertebrae and femur were measured by using a PIXImus Bone Densitometer System. Intervertebral disc proteoglycan was measured with the DMMB assay. Histologic analysis of proteoglycan for IVD and articular cartilage was performed with safranin O staining, and degeneration parameters were scored.

RESULTS:
The lumbar BMC was significantly increased in female swimmers at both the highest and lowest dose of DES, whereas the femoral BMC was increased only at the highest. The males, conversely, showed a decreased BMC at the highest dose of DES for both lumbar and femoral bone. The female swim group had an increased BA at the highest dose of DES, whereas the male counterpart showed a decreased BA for femoral bone. The TBA showed a similar pattern. Proteoglycan analysis of lumbar IVDs showed a decrease at the lowest doses but a significant increase at the highest doses for both males and females. Histologic examination showed morphologic changes of the IVD and articular cartilage for all doses of DES.

CONCLUSIONS:
DES significantly affected the musculoskeletal system of adult mice. Results suggest that environmental estrogen contaminants can have a detrimental effect on the developmental lumbar bone growth and mineralization in mice. Further studies measuring the impact of environmental estrogen mimics, such as bisphenol A, are then warranted.

Sources and Full Study
  • Effect of in utero exposure to diethylstilbestrol on lumbar and femoral bone, articular cartilage, and the intervertebral disc in male and female adult mice progeny with and without swimming exercise, NCBI PMID: 22269139, 2012 Jan 23;14(1):R17. doi: 10.1186/ar3696.
  • Full study, PMC3392807, 2012;14(1):R17. doi:10.1186/ar3696.
More DES DiEthylStilbestrol Resources

Diagnostic chest radiation before age 30 may increase breast cancer risk

Choose MRI scan over x-ray and mammogram

The BMJ logo image
Women advised – via the BMJ in 2012 – to choose MRI scan over x-ray and mammogram.

Women carrying a mutation in the BRCA1- or BRCA2- genes (which control the suppression of breast and ovarian cancer) who have undergone diagnostic radiation to the chest before the age of 30 are more likely to develop breast cancer than those who carry the gene mutation but who have not been exposed, a study published on bmj.com today reveals.

The BMJ published a commentary in August which argued that a breast cancer charity was using misleading statistics to persuade women to undergo mammography, concluding that charities should stop generating false hope and that women need and deserve the facts instead.

Exposure to radiation is an established risk factor for breast cancer in the general population. Some studies have suggested that women with a mutated BRCA1/2 gene may have increased radiation sensitivity because BRCA1 and BRCA2 are the genes involved in the repair of DNA breaks, which can be caused by radiation. The benefit from mammographic screening in young BRCA1/2 mutation carriers may therefore not outweigh the radiation risk. Some countries have even gone as far as recommending that women avoid mammographic screening before the age of 30 but results of studies have been inconsistent.

Authors from the Netherlands Cancer Institute therefore looked at 1993 female BRCA1/2 mutation carriers in the Netherlands, France and the UK between 2006 and 2009 to see whether variations in DNA increase the chances of radiation-induced breast cancer risk. Follow-up ended with diagnosis of first breast cancer. All patients were aged 18 or over.

Women were questioned on exposure via x-ray or mammogram, age at first exposure, number of exposures before age 20, at ages 20-29, 30-39 and age at last exposure.

Results showed that 43% (848) of the 1993 women were diagnosed with breast cancer. 48% (926) reported ever having an x-ray and 33% (637) a mammogram. The average age at first mammogram was 29 years. A history of any exposure to diagnostic or screening radiation to the chest at ages 20 to 29 increased breast cancer risk by 43% and any exposure before the age of 20 increased breast cancer risk by 62%. No association with breast cancer was apparent for exposures at ages 30-39.

For every 100 BRCA1/2 mutation carriers aged 30, nine will have developed breast cancer by the age of 40 and the number of cases would increase by five if all had had one mammogram before age 30. The authors do say however that this estimate “should be interpreted with caution because there were few women with breast cancer who had had a mammogram before age 30 in the study”.

The authors conclude that “exposure to diagnostic radiation before age 30 was associated with an increased breast cancer risk in BRCA1/2 mutation carriers”. They say however due to “puzzling” findings in the differences between breast cancer risk for BRCA1 and BRCA2 carriers, larger studies are needed to determine whether a difference does in fact exist. The authors recommend non-ionizing radiation imaging techniques, such as MRI, for mutation carriers.

Sources and More Information:

  • Diagnostic Radiation Exposure May Raise Breast Cancer Risk in Some BRCA1/2 Mutation Carriers, NCI.
  • Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK), BMJ 2012;345:e5660, 06 September 2012.
  • Diagnostic chest radiation before age 30 may increase breast cancer risk in BRCA1/2 mutation carriers, BMJ press release, 05 September 2012.

The Intersection of Neurotoxicology and Endocrine Disruption

BPA and phthalates associations with brain sexual differentiation are reviewed and further questions noted.

Abstract

image of ncbi logo
BPA and phthalates associations with brain sexual differentiation are reviewed and further questions noted.

Endocrine disruption, the guiding theme of the 27th International Neurotoxicology Conference, merged into the neurotoxicology agenda largely because hormones help steer the process of brain development. Although the disruption motif first attracted public health attention because of reproductive anomalies in both wildlife and humans, the neurobehavioral implications had been planted decades earlier. They stemmed from the principle that sex differences in behavior are primarily the outcomes of differences in how the brain is sexually differentiated during early development by gonadal hormones (the Organizational Hypothesis). We also now understand that environmental chemicals are capable of altering these underlying events and processes. Among those chemicals, the group labeled as endocrine disrupting chemicals (EDCs) offers the clearest evidence of such selectivity, a consequence of their actions on the endogenous sex steroids, androgens and estrogens. Two EDCs in particular offer useful and intriguing examples. One is phthalate esters. The other is bisphenol A (BPA). Both agents are used extensively in plastics manufacture, and are pervasive in the environment. Both are produced in immense quantities. Both are found in almost all humans. Phthalates are considered to function in essence as anti-androgens, while bisphenol A is labeled as an estrogen. Their associations with brain sexual differentiation are reviewed and further questions noted. Both EDCs produce a wider spectrum of health effects, however, than would be extrapolated simply from their properties as anti-androgens and estrogens. Obesity is one example. Further complicating their assessment as health risks are questions about nonmonotonic dose-response functions and about transgenerational effects incurred via epigenetic mechanisms. All these facets of endocrine disruption are pieces of a puzzle that challenge neurotoxicologists for solutions.

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Team IGEM Bielefeld built a Synthetic Biofilter to Remove Estrogens from Drinking Water

This project has the potential to solve problems of micro contaminations in sewage water

Removing Estrogen from Drinking Water

image of a sewage plant
Sewage Plant in Bielefeld – Hundreds of samples were needed to reach success: The synthetic biofilter developed by Bielefeld University’s iGEM team can filter out estrogens from contaminated water.

The birth control pill is a widespread contraception method. However, large amounts of these modified estrogens leave the body again in urine. The conventional methods in sewage treatment plants are unable to treat this waste water sufficiently because the most frequently used estrogen ethinylestradiol is very difficult to break down. As a result, the hormone finds its way into rivers and lakes and also accumulates in drinking water with serious consequences for fish and other aquatic life. These range from reproductive and severe developmental disorders to the formation of female sexual characteristics in males. The long-term consequences of increasing estrogen pollution for human beings are still largely unknown. Nonetheless, declining sperm counts and thereby increasing infertility in men living in industrial nations may well relate to this hormonal pollution. In addition, testicular and prostate cancers as well as osteoporosis (a reduction in bone density) could be a consequence of overly high concentrations of estrogen in the human body. The goal of the Bielefeld iGEM team is to develop a biological filter in which certain enzymes (so-called laccases) break down the estrogen.

Bielefeld students on a par with teams from international elite universities

Months of painstaking work in the laboratory at Bielefeld University‘s Center for Biotechnology (CeBiTec) have paid off: the 15 students participating in this year’s ‘international Genetically Engineered Machine competition’ (iGEM) at the Massachusetts Institute of Technology (MIT) have good reason to celebrate. The goal of their project was to develop a biological filter that removes estrogen from drinking water. It was a success: they managed to produce enzymes that break down the hormone. On Monday 5 November, the competition finals came to a close in Boston. From 190 teams throughout the world, Bielefeld’s students made it through to the ‘Sweet Sixteen’, the selection of the 16 best teams in the company of teams from such prestigious universities as Stanford University (USA), the Canadian University of Calgary, and Jiaotong University in Shanghai, China.

More than 70 teams from throughout the world got through to the finals of the top student competition in synthetic biology. The Bielefeld team was one of five German teams at the start. Bielefeld University has now participated in the iGEM competition for the third year running and already succeeded in qualifying for Boston in 2010 and 2011. This year’s team, like its predecessors, made it into the ‘Sweet Sixteen’. ‘We stand in direct comparison with universities like Stanford and Cornell. At first, that seemed very intimidating, but we soon noticed they were having to fight exactly the same problems as we were. And with our know-how, we can match the pace here’, says Moritz Müller, a master student of molecular biotechnology.

Enzymes from fungi growing on trees filter out medicine residues from sewage and drinking water

Conventional methods of filtering waste water in sewage treatment plants are unable to completely remove medicine residues such as the estrogens in birth control pills. These residues then find their way into rivers and lakes and also accumulate in our drinking water. For fish and other aquatic life, estrogens can lead to reproductive and developmental disorders and even to the formation of female characteristics in males. The potential long-term consequences for human beings – declining sperm counts, infertility, various cancers, and osteoporosis – are still largely unknown.

The Bielefeld iGEM team has developed a biological filter in which specific enzymes (so-called laccases) break down these medicine residues. One known source of particularly efficient laccases is the turkey tail, a type of fungus that grows on trees. Using methods from synthetic biology, the students succeeded in synthesizing this enzyme and applying it to filter material. ‘We didn’t want to invent something totally crazy with our project – just because it’s technically feasible. We wanted to do something that could actually be put to use in the near future, perhaps in 20 years, and be a real benefit’, explains Robert Braun, a master student of molecular biotechnology. ‘The biofilter is such a project. And we have shown that our idea works. In principle, a company could now come along and develop our filter further. We ourselves have got to get back to our studies – most of us have rather neglected them for the last 6 months. However, the experiences we have gathered more than compensate for that’.

International competition

The iGEM competition has been held every year since 2003 by the Massachusetts Institute of Technology (MIT) in Boston. Starting as an MIT study course, the number of competitors has grown rapidly from five teams in 2004 to 190 in the present year. All teams face the same task: taking their project from the idea across the laboratory work to gaining funding and communicating the findings. On the student level, the iGEM can be seen as the world championship in synthetic biology that shows the future potential of this still young field of research. The Bielefeld iGEM team is being funded by Bielefeld University‘s Center for Biotechnology (CeBiTec) and the BIO.NRW Cluster Biotechnology North Rhine-Westphalia.

Sources:
  • TOXIC COMPOUNDS IN NATURAL WATER – A CASE FOR LACCASE, Team:Bielefeld-Germany, 2012.
  • Synthetic biofilter wins through to the top ‘Sweet Sixteen’ in Boston, ekvv.uni news, Nov 2012.
  • Removing estrogen from drinking water, Phys.org News, June 2012.