Prenatal DES induces malformation of external genitalia of male and female mice in two generations

DiEthylStilbestrol transgenerational effects on the genital tract

Highlights:

Elsevier logo image
Prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.
  • Objective criteria of prenatally DES-induced adult mouse hypospadias are presented for the first time.
  • The incidence of penile and preputial hypospadias was higher in C57BL/6 versus CD-1 mice consistent with enhanced estrogen sensitivity of C57BL/6 mice.
  • The incidence of urethral–vaginal fistula was similar in prenatally DES-treated mice of both strains.
  • Prenatally DES-induced male hypospadias and urethral–vaginal fistula were transmitted to second-generation mice.

Abstract:

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18.Mice were examined at birth, and on 5–120 days postnatal to evaluate ExG malformations.

Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral–vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations.

For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral–vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal.

Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Sources

  • Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains, ScienceIndex, stories/4604450, 18 Oct 2014.
  • Full text: Elsevier, article/pii/S0301468114000553, DOI: 10.1016/j.diff.2014.09.005.
More DES DiEthylStilbestrol Resources

Effects of Prenatal Exposures to EDCs on Childhood Development

By the Collaborative on Health and the Environment

Dr. Frederica Perera on the Effects of Prenatal Exposures to EDCs on Childhood Development.

The call featured Dr. Frederica Perera who reviewed data from a longitudinal cohort study following mothers and children from pregnancy into adolescence. In this study, prenatal exposure to the combustion related air pollutants, polycyclic aromatic hydrocarbons, is associated with adverse neurodevelopmental outcomes as well as other disease endpoints. Prevention strategies were also discussed.

Sources:

Additional resources of interest:
    • Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children  PDF.
    • Prenatal airborne polycyclic aromatic hydrocarbon exposure and child IQ at age 5 years PDF.
    • Prenatal Polycyclic Aromatic Hydrocarbon (PAH) Exposure and Child Behavior at age 6-7 PDF.
    • Prenatal Exposure to Air Pollution, Maternal Psychological Distress, and Child Behavior PDF.
    • Prenatal Exposure to Polycyclic Aromatic Hydrocarbons, Benzo[a]Pyrene-DNA Adducts and Genomic DNA Methylation in Cord Blood PDF.
    • Children’s environmental health: a critical challenge of our time PDF. PDF.

Comparative effects of neonatal DES on external genitalia development in adult male mice

Many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development

Highlights:

Elsevier logo image
This 2014 study suggests that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development.
  • Prenatal DES treatment of C57BL/6 and CD-1 mice elicited a broad spectrum of penile and preputial malformations that were consistently more severed in C57BL/6 mice having enhanced estrogen sensitivity.
  • Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues.
  • The developmental basis of several adult DES-induced malformations was presented.

Abstract:

Neonatally DES-induced penile and preputial hypospadias are suggested to be due to impaired growth and tissue fusion events during development.

The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation.

CD-1 and C57BL/6 litters were injected with sesame oil or DES (200ng/g/5μl in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal.

Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following:

  • severe truncation of the prepuce and glans penis,
  • an abnormal urethral meatus,
  • ventral tethering of the penis,
  • reduced os penis length and glans width,
  • impaired differentiation of cartilage,
  • absence of urethral flaps,
  • impaired differentiation of erectile bodies.

Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice.

We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development.

Sources

  • Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity,
    ScienceDirect, stories/4607851, 18 Oct 2014.
  • Full text: Elsevier, article/pii/S0301468114000541, DOI: 10.1016/j.diff.2014.09.004.
More DES DiEthylStilbestrol Resources

Pledge to be an Antibiotic Guardian

Get Your Antibiotic Guardian Certificate

What is antibiotic resistance, and why should we care? Video published on 18 Sep 2014 by Public Health England.

Make your pledge today and become an antibiotic guardian
Antibiotic Guardian campaign logo
I have pledged to be an #AntibioticGuardian for #EAAD2014. You can make a pledge too here.

Antibiotic Guardian, an initiative developed by Public Health England (PHE) is urging members of the public and healthcare professionals to join in the campaign and take action and help make sure antibiotics work now and in the future.

To become an Antibiotic Guardian people choose and enact a pledge about how they will make better use of antibiotics. This campaign forms part of activities that support European Antibiotic Awareness Day (EAAD).

The website asks users to choose which category they would like to make a pledge in. For healthcare professionals and leaders, there are 10 categories from GPs, nurses, vets, commissioners, government officials and public health specialists. For members of the public there are 4 choices including parents of small children, pet owners and farmers. The available pledges change per category and those responding will be asked if PHE can follow-up to confirm they did keep their pledge.

For example, members of the public can choose from a range of pledges, including the following:

  • the next time I have a cold or flu I pledge to try treating the symptoms for 5 days rather than going to the GP
  • the next time I have a cold or flu I will talk to the pharmacist first about how I can treat their symptoms rather than making a GP appointment
  • It is vital we prevent antibiotics from getting into the environment. I pledge to always take any unused antibiotics to my pharmacy for safe disposal

And GPs can choose, among others:

  • when I see a patient with a self-limiting illness, I will discuss methods of controlling symptoms rather than prescribing antibiotics
  • when I see a child with a respiratory tract infection (coughs, colds, sore throats, and ear aches) I will use the TARGET guide to treat your infection booklet rather than prescribe antibiotics
  • the next time I intend to prescribe antibiotics for a self-limiting infection to a patient with high expectations of antibiotic treatment, I will use a delayed/backup prescription

Healthcare leaders can choose; among others:

  • I will visit my local hospital, community pharmacy or general practice surgery to show support for European Antibiotics Awareness Day during EAAD week (18 to 22 November 2014)
  • I will ensure that the executive team and board are regularly informed about Antimicrobial Stewardship and AMR in my Trust
  • I pledge to incorporate Antimicrobial Stewardship and Resistance as a quality measure within my commissioning pathways (including out of hours)
Dr Diane Ashiru-Oredope,
Lead for EAAD 2014 at Public Health England, said:

Everybody can help to tackle antibiotic resistance and we really urge people to help us do this. There is a lot to be done but we can start by making inroads into inappropriate prescribing.

There are 2 elements to this. One is that we need patients to not always expect to receive an antibiotic for those self-limiting illnesses which are typically caused by viruses. This generally includes those where the symptoms include coughs, runny noses, muscle aches and fever. And the other is for GPs not to feel pressurised into prescribing antibiotics when they aren’t really necessary.

Community pharmacists and their teams also have a key role and should be seen as the first port of call for many winter illnesses caused by viruses. They can also help to manage patients’ expectations by explaining the normal duration of these symptoms, what warning signs to look out for and providing effective over the counter treatments that will help relieve the symptoms. “

Nicholas Brown,
President at the British Society for Antimicrobial Chemotherapy (BSAC), said:

Recently published research in BSAC’s Journal, Journal of Antimicrobial Chemotherapy, confirms that despite government recommendations to reduce prescribing for viral illnesses there are still many GPs who do this. Of course GPs don’t want their patients to feel unwell but there are many medicines which are available over-the-counter which can really help to reduce symptoms and make people feel better.

We want to encourage everyone to self-treat as much as possible when it is safe and appropriate to do so. By using antibiotics only when they are needed we can all help to make sure that we keep our antibiotics working for everyone in the future.

Antibiotic resistance is one the biggest threats to public health and PHE is delivering 4 key aspects of the 5-year UK strategy to help combat antibiotic resistance. These are improving infection prevention and control practices to reduce the number of infections in patients; optimising prescribing practice, improving professional education, training and public engagement and enabling better access to and use of surveillance data. “

Public Health England Reports:

  • Join over 1,500 antibiotic guardians: choose a pledge today to help tackle antibiotic resistance, press release, 10 October 2014.
  • Antibiotic resistance is one of the biggest threats facing us today, antibioticguardian.com
  • European Antibiotic Awareness Day: 2014 resources, EAAD2014.
  • New report reveals increase in use of antibiotics linked to rising levels of antibiotic resistance, press release, 10 October 2014.
  • English surveillance programme antimicrobial utilisation and resistance report 2014.
  • UK 5 Year Antimicrobial Resistance Strategy 2013 to 2018, PDF 2013.
  • Infections and the rise of antimicrobial resistance report 2013.
2014 UK Newspapers Headlines:
2013 UK Newspapers Headlines:

Antibiotic resistance continues to rise due to increase in use in the UK

Despite warnings, the number of antibiotic prescriptions in the UK continues to soar, as do new cases of resistant bacteria

Gov.UK logo image
Gov.UK official press release: combined GP and hospital prescribing up 6% between 2010 and 2013. Levels of antibiotic resistance also up.

A new report from Public Health England (PHE) found that between 2010 and 2013 there was a 6% increase in the combined antibiotic prescribing of GPs and hospitals. There was also an increase of 12% in the number of bloodstream infections caused by E.coli with varying levels of resistance to key antibiotics for this infection of between 10 to 19%.

These data are from the first annual report of PHE’s English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR), published today (10 October 2014).

While the proportion of resistant infections remains the same as that seen in previous years, as the total number of infections has increased so the total number of resistant infections has risen. The report also shows a wide variation in both prescribing habits and antibiotic usage across England.

Key findings:

  • between 2010 and 2013 total antibiotic consumption (GPs and hospitals) rose by 6% from 25.9 to 27.4 daily defined dose* per 1,000 inhabitants per day
  • over the same 4-year period GP prescribing rose by 4%, prescribing to hospital inpatients rose by 12% and other community prescriptions (dentists and other non-GP prescribing) rose by 32%. This latter area is of concern and needs to be further examined
  • the increasing number of E.coli bloodstream infections has seen a corresponding increase in levels of resistance to a number of key antibiotics
  • higher rates of resistance were seen in those areas with higher rates of prescribing
  • there was a difference in prescribing between the north and south of the country. This is an area that needs more investigation but some of the differences may be due to deprivation, higher rates of smoking, co-morbidities, and other factors
  • the highest levels of GP prescribing were seen in Durham, Darlington and Tees which was over 40% higher than London (26.5 versus 18.9 daily defined dose per 1,000 inhabitants). However, this may be due to access to healthcare in London (with people attending hospitals instead of GP practices to access treatment), as London has the highest amount of hospital prescribing per population
Lead author Dr Susan Hopkins,
healthcare epidemiologist at PHE, said:

This publication marks a real move forward in our understanding of antibiotic prescribing habits as it is the first time that both GP and hospital prescribing data have been collated in one document and prescribing trends analysed.

The aim now must be to reduce levels of prescribing back to that seen in 2010. There are already a number of different activities going ahead to support this including the development of quality measures for prescribing. This will enable local clinical commissioning groups to monitor the prescribing of hospitals and surgeries in their area and see how they compare against a benchmark. They will also be responsible for taking action against inappropriate prescribing in their area.

In addressing the issue of antibiotic resistance it is important to look at the whole healthcare economy approach. There is a lot of work going on to address the problem of antibiotic resistance but we must not underestimate how much work needs to be done to turn the tide and get levels of resistance down. ”

Professor John Watson,
deputy chief medical officer at the Department of Health, said:

Antimicrobial resistance is one of the biggest threats to health security facing the world today and everybody must take action. We want to support all doctors and other prescribers in reducing their prescribing rates where possible. These data will play an important part in highlighting regional variations in prescribing. ”

Professor Anthony Kessel,
director of international public health at PHE, said:

We cannot underestimate the importance of this report. Antibiotic resistance is one of the biggest threats of our time and understanding more about who is prescribing and what is being prescribed is the first step to helping us make improvements.

In England we are progressing and implementing a raft of tools to help us reduce the levels of prescribing and resistance and these include benchmarking, accountability on prescribing and quality measures. We are also asking everyone in the UK, the public and the medical community, to join our campaign and become an Antibiotic Guardian. We want everyone to choose one simple pledge about how they make better use of antibiotics and help save these vital medicines from becoming obsolete.

ESPAUR was established as a response to the UK cross government 5-year strategy to address the growing problem of antibiotic resistance. The report focuses on the use of antibiotics, stewardship and levels of resistance by NHS area team across GP practices and hospitals (primary and secondary care).

Public Health England Reports:

  • New report reveals increase in use of antibiotics linked to rising levels of antibiotic resistance, press release, 10 October 2014.
  • English surveillance programme antimicrobial utilisation and resistance report 2014.
  • UK 5 Year Antimicrobial Resistance Strategy 2013 to 2018, PDF 2013.
  • Infections and the rise of antimicrobial resistance report 2013.
2014 UK Newspapers Headlines:
2013 UK Newspapers Headlines:

 

Endocrine Disruption of the Neuro-immune Interface

By the Collaborative on Health and the Environment

Dr. Jamie DeWitt describes scenarios where endocrine disrupting chemicals can alter brain development by changing signals to the immune cells that can mediate development of sex specificity in the brain.

Building on the January 8, 2014 teleconference featuring Dr. Rodney Dietert  on how the developing immune system is a target for endocrine disrupting chemicals, Dr. Jamie DeWitt discussed how certain cells of the immune system may mediate endocrine signals to direct aspects of brain development. She also described scenarios where endocrine disrupting chemicals can alter brain development by changing signals to the immune cells that can mediate development of sex specificity in the brain.

Sources:

Additional resources of interest:
  • Suppression of Humoral Immunity by Perfluorooctanoic Acid is Independent of Elevated Serum Corticosterone Concentration in MicePDF
  • Current Status of Developmental Immunotoxicity: Early-Life Patterns and TestingPDF
  • Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune PerspectivesPDF
  • Bisphenol A: Developmental Toxicity from Early Prenatal ExposurePDF

Endocrine Disruption and Immune Dysfunction

By the Collaborative on Health and the Environment

Dr. Rodney Dietert discussed how the immune system is a target for endocrine disrupting chemicals, particularly during development.

On this first in a series of calls on endocrine disrupting chemicals, Dr. Rodney Dietert discussed how the immune system is a target for endocrine disrupting chemicals, particularly during development. Numerous relatively ‘hidden’ effects can ensue from a single risk factor and emerge over a lifetime. He also discussed how current safety testing fails to appropriately assess misregulated inflammation as the greatest immune based health risk.

Sources:

Investigating the association between central obesity (using skirt size) and breast cancer risk

Association of skirt size and postmenopausal breast cancer risk in older women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening

Abstract

The BMJ logo image
Increased breast cancer risk – by a third – for women who go up a skirt size as they get older, study suggests… expanding waistline for women is a warning for higher breast cancer risk..

Objectives
Several studies suggest that overall and central-obesity are associated with increased breast cancer (BC) risk in postmenopausal-women. However, there are no studies investigating changes of central obesity and BC. We report on the association of BC risk with self-reported skirt size (SS; waist-circumference proxy) changes between 20s and postmenopausal-age.

Design
Prospective cohort-study.

Setting
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) involving the nine trial centres in England.

Participants
Postmenopausal-women aged >50 with no known history of BC prior to or on the day of completion of the study-entry questionnaire.

Interventions
At recruitment and at study entry, women were asked to complete a questionnaire. Women were followed-up via ‘flagging’ at the NHS Information Centre in England and the Hospital Episode Statistics.

Main outcome-measure
Time to initial BC diagnosis.

Results
Between 2 January 2005 and 1 July 2010, 92 834 UKCTOCS participants (median age 64.0) completed the study-entry questionnaire. During median follow-up of 3.19 years (25th–75th centile: 2.46–3.78), 1090 women developed BC. Model adjusted analysis for potential confounders showed body mass index (BMI) at recruitment to UKCTOCS (HR for a 5 unit change=1.076, 95% CI 1.012 to 1.136), current SS at study entry (HR=1.051; 95% CI 1.014 to 1.089) and change in SS per 10 years (CSS) (HR=1.330; 95% CI 1.121 to 1.579) were associated with increased BC risk but not SS at 25 (HR=1.006; 95% CI 0.958 to 1.056). CSS was the most predictive singe adiposity measure and further analysis including both CSS and BMI in the model revealed CSS remained significant (HR=1.266; 95% CI 1.041 to 1.538) but not BMI (HR=1.037; 95% CI 0.970 to 1.109).

Conclusions
CSS is associated with BC risk independent of BMI. A unit increase in UK SS (eg, 12–14) every 10-years between 25 and postmenopausal-age is associated with postmenopausal BC risk by 33%. Validation of these results could provide women with a simple and easy to understand message.

Strengths and limitations of this study

  • To the best of our knowledge, this is the first study investigating the association between central obesity using skirt size (SS) as a proxy and breast cancer risk. Between 25 and postmenopausal age, an increase in SS by one unit every decade increased the risk of postmenopausal breast cancer by 33% while decrease in SS was associated with lowering of risk.
  • Our prospective cohort-study includes 94 000 women with comprehensive follow-up through data linkage to multiple national databases.
  • There is a possibility of underestimation of self-reported SS. However, if current SS at study entry is uniformly underestimated then there is merely rescaling of CSS so that the strength of the association is unaffected. Furthermore, recall bias of the SS at 25 maybe a limitation but unless this inability in reporting is systematically related to future breast cancer, measurement error can only result in underestimating the strength of the true association between CSS and breast cancer risk.
  • Given that obesity is now emerging as a global epidemic, from a public health prospective these findings are significant as they provide women with a simple and easy to understand message.
Sources and More Information:
  • Association of skirt size and postmenopausal breast cancer risk in older women: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), BMJ Open 2014;4:e005400 doi:10.1136/bmjopen-2014-005400, 24.09.2014.
  • Skirt size increase ups breast cancer risk, NHS Choices, Cancer, September 25 2014.

About Half of Cancers are caught too late in England

Analysis of the financial implications of achieving earlier diagnosis of colorectal, lung and ovarian cancer

Cancer Research UK logo image
Half of cancers in England diagnosed at late stage as a report prepared for Cancer Research UK shows that early diagnosis saves lives and could save the NHS millions of pounds.

A Cancer Research UK analysis out today reveals that 46 per cent of cancers in England are diagnosed at an advanced stage, when they are harder to treat successfully.

The figures come as a new report shows that if all areas diagnosed cancers as early as the best in England, for four types of cancer alone, this could save the NHS over £44 million in treatment costs and benefit over 11,000 patients each year. Extrapolating this to all types of cancer would imply an annual saving of nearly £210m, while helping to improve the survival prospects for more than 52,000 patients. ”

Sources and More Information:

  • Half of cancers diagnosed at late stage as report shows early diagnosis saves lives and could save the NHS money, CancerResearchUK, Press release, 22 September 2014.
  • Saving lives, averting costs,
    A report prepared for Cancer Research UK, September 2014.
  • Late cancer diagnosis ‘costing lives and money’, NHS Choices, cancer, September 22 2014.

Maternal BPA programs Offspring Metabolic Syndrome

By the Collaborative on Health and the Environment

Prenatal exposure to EDCs, specifically the plastic component BPA, can increase the relative risk of adult obesity and metabolic syndrome.

On this call Drs. Ross and Desai presented evidence that prenatal exposure to endocrine disrupting chemicals (EDCs), specifically the plastic component bisphenol A, can increase the relative risk of adult obesity and metabolic syndrome.
They also discussed the significance of these findings for neonatal and childhood care, and the need for strategies for the prevention and therapy of obesity to address programming effects of the early life environment.

Sources: