Happy Anniversary DES Daughter Network

Thank you all for your support over the years !

Time flies ; we registered DES Daughter Network blog on WordPress.com 5 years ago already!

Thank you for your support over the years and for all your comments left.
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And now, it’s time time for some stats…

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Do we Reach the Whole World? Yes!

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NB: This blog is the “little sister” of this one ; which fully focuses on the DES tragedy…  cheers

Low-dose and combined effects of oral exposure to BPA and DES on the male reproductive system

Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population

Abstract

Study of the joint action of xenobiotics is important to fully explore their toxicity and complete risk analysis. In this study, we investigated the effects of low-dose and combined exposure of Bisphenol-A (BPA) and diethylstilbestrol (DES) on the reproductive system in adult male rats.

The results showed that the sperm motility decreased in the BPA/DES and combined groups. Sperm deformity ratios and histological lesions of the testes were significantly higher and more significant, respectively, in the combined group compared with the single treated groups. No dose-effect relationship or significant additive effect on serum hormone levels was observed after combined exposure to BPA/DES. Ultrastructural results showed lesions of the Sertoli and Leydig cells, mainly in the endoplasmic reticulum (ER), in all treated groups. ER stress molecular sensor IRE1 was phosphorylated and activated after BPA and DES treatment in this study.

Low-dose and combined effects of oral exposure to bisphenol A and diethylstilbestrol on the male reproductive system in adult Sprague-Dawley rats, NCBI pubmed/26970683, doi: 10.1016/j.etap.2016.02.014, 2016 Feb 24.

The protein levels of ES stress molecular marker CHOP were significantly up-regulated after exposure to BPA, DES, and BPA and DES combined.

These findings indicate that ER stress is important in BPA/DES-induced damage in rat testes. Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population.

More DES DiEthylStilbestrol Resources

BIA-10-2474: Lessons learnt from the fatal French study

Do not test in humans drugs that lack an identified therapeutic potential

Abstract

In January the phase I study of the drug BIA-10-2474 conducted in Rennes, France, left one initially healthy volunteer dead and three with serious neurological damage, some of which may be permanent.

This was a not unusual phase 1 study of a new wannabe drug and included four substudies:

  • single ascending doses,
  • multiple ascending doses,
  • a food interaction study,
  • and some pharmacodynamic testing looking for potential indications.

Dose escalation was based on pharmacokinetic data from animal studies and from the previous series in this phase I study.

The study of single ascending doses took place uneventfully up to the maximum dose of 100 mg. The first four series of multiple ascending doses had no problem up to 20 mg for 10 days. Suddenly, on the fifth day of the fifth series (50 mg daily) one participant developed neurological problems and was admitted to hospital. The next day the other participants received their treatment. Three of the four remaining participants had neurological symptoms and were admitted to hospital. They recovered, some with severe sequelae, but the first participant died. ” …

This recent story reminded me the 1950 tragedy study at the University of Chicago, where every pregnant woman at the University’s Lying-In Hospital (1,646) was a test subject for a DES experiment without their knowledge or consent, and became part of a clinical trial: one-half were randomized to receive DES and the other half received placebos. None of the women were told they were part of a study, nor were they told what drug they were taking. The study found that twice as many of the DES-treated mothers had miscarriages, premature births, small babies, …

Chemicals in broken test tube, Iwan Gabovitch.

Continue reading Lessons from the fatal French study BIA-10-2474BMJ 2016;353:i2727, 18 May 2016.

Related Press Releases
  • The fatal BIA 10-2474 trial and lessons learned, martinalutter, 20 April 2016.
  • BIA 10-2474 saga continues – who knew what and when – and nobody comes out a winner, collabchem, 13 April 2016.
  • BIA 10-2474: Expert calls for better pharmacology before protocols are approved, in-pharmatechnologist, 16-Mar-2016.
  • A double-blind, randomised, placebo-controlled, combined single and multiple ascending dose study including food interaction, to investigate the safety, tolerability, pharmacokinetic and pharmacodynamie profile of BIA 10-2474, in healthy volunteers, Clinical Study Protocol N° BIA-102474-101.
  • Report by the Temporary Specialist Scientific Committee (TSSC), “FAAH (Fatty Acid Amide Hydrolase)”, on the causes of the accident during a Phase 1 clinical trial in Rennes in January 2016 (25/04/2016), ansm.

Les eurodéputés contaminés au glyphosate

Le taux de glyphosate moyen présent dans les urines des eurodéputés est 17 fois plus élevé que la normale

Les eurodéputés contaminés au glyphosate, EurActiv, May 13, 2016.

” À quelques jours du vote des États membres sur le glyphosate, des tests réalisés sur 48 eurodéputés révèlent que leurs urines contiennent un taux parfois 35 fois supérieur au seuil limite.

“Tous les participants avaient du glyphosate dans les urines, et ce, dans des proportions élevées.

La moyenne du taux de glyphosate dans l’urine des députés européens est de 1,7 microgrammes/litre alors que la norme d’eau potable européenne est de 0,1 microgrammes/litre. “

conclut le laboratoire Biocheck de Leipzig, qui a effectué le test sur 48 députés du Parlement européen, tous sexes et tous partis confondus. Au total, 13 pays sont représentés, dont la Belgique, la République tchèque, la France, la Hongrie, l’Espagne, la Finlande et l’Italie, entre autres.

Uriner dans un tube et pisser dans un violon, histoire de la réautorisation du glyphosate en Europe, huffingtonpost, 18/05/2016.

Cette opération coup de poing, lancée par une dizaine d’eurodéputés, révèle que le taux de glyphosate moyen présent dans les urines des eurodéputés est 17 fois plus élevé que la normale. ” …

… lisez l’entièreté de l’article sur EurActiv.

In-utero DES exposure and cardiac structure/function alteration

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

Abstract

Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs.

Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart.

Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart.

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny, article/pii/S0041008X12004607, 1 January 2013.

Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged.

We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males.

More DES DiEthylStilbestrol Resources

How targeted exercise can help fight cancer

Exercise during cancer treatment : a potential game changer

Video published on 10 May 2016 by ABCTVCatalyst channel.

It’s long been understood that exercise decreases the risk of developing cancer but a radical idea for patients to exercise during cancer treatment has been labelled a potential game changer by some doctors.

  • By the time you hit midlife, odds are you or someone close to you will be touched by cancer. Cancer remains a potentially lethal lottery and everyone’s experience is different. But appropriate exercise under professional supervision – before, during, or after treatment – seems to substantially improve your odds.
    Catalyst meets a group of cancer patients that is experiencing extraordinary benefits from prescribed targeted exercise programs.
  • Watch our medical research video playlist.

 

 

BPA In-Utero Exposure and Obesity at very young age

Children whose mothers had higher BPA exposure in their third trimester had more body fat in their school-age years

More BPA exposure as a fetus leaves kids fatter at age 7 – NYC study, environmentalhealthnews, May 17, 2016.

More BPA exposure before birth could mean more body fat and larger waists during early childhood, according to a New York City recent study.

” The prenatal window is a time when there really should be caution exerted for unnecessary exposures. “

said Lori Hoepner, investigator at the Columbia Center for Children’s Environmental Health and assistant professor at SUNY Downstate Medical Center.

Abstract

Bisphenol A and Adiposity in an Inner-City Birth Cohort, ehp, 17 May 2016.

Child & blackbirds, Chris Sloan.

Background:
Early life exposure to the endocrine disruptor bisphenol A (BPA) may contribute to development of obesity. Prospective evidence in humans on this topic is limited.

Objectives:
We examined prenatal and early childhood BPA exposures in relation to childhood measures of adiposity in the Columbia Center for Children’s Environmental Health (CCCEH) New York City birth cohort.

Methods:
BPA concentrations were measured in prenatal (n=375) and child ages 3 (n=408) and 5 years (n=518) spot urine samples. Childhood anthropometric and bioelectrical impedance outcomes included body mass index z-scores (BMIZ) at 5 and 7 years, and fat mass index (FMI), percent body fat (%BF), and waist circumference (WC) at 7 years. Associations were evaluated using multiple linear regression with continuous and tertile BPA concentrations.

Results:
Prenatal urinary BPA concentrations were positively associated with child age 7 FMI (beta=0.31 kg/m2, p-value=0.04, [95%CI 0.01, 0.60]), %BF (beta=0.79, p-value=0.04, [95%CI 0.03, 1.55]), and WC (beta=1.29 cm, p-value=0.01, [95%CI 0.29, 2.30]), but not BMIZ, or change in BMIZ between ages 5 and 7 years (all p-values > 0.1). FMI results were sex-specific. Child urinary BPA concentrations were not associated with child anthropometric outcomes (all p-values > 0.05).

Conclusions:
Analyses of the CCCEH longitudinal birth cohort found associations between prenatal urinary BPA concentrations and FMI, %BF and WC. Our results suggest that prenatal BPA exposure may contribute to developmental origins of adiposity. These findings are consistent with several prior studies, raising concern about the pervasiveness of BPA.

Disrupting autophagy, a cellular housekeeping process, limits cancer spread

Stopping cancer in its tracks

Stopping cancer in its tracks, The University of Chicago Medical Center, May 12, 2016.

Spreading cancer can be halted by blocking a key mechanism that allows tumour cells to break free from their birthplace.

Researchers from the University of Chicago have shown that inhibiting autophagy, a self-devouring process used by cells to degrade large intra-cellular cargo, effectively blocks tumor cell migration and breast cancer metastasis in tumor models.

Introduction

Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastatic Tumor Cells through the Direct Interaction of Paxillin with LC3, Cell Reports S2211-1247(16)30509-5, May 12, 2016.

Macro-autophagy (hereinafter termed autophagy) is a catabolic process important for the degradation of damaged organelles and protein aggregates, as well as the intracellular recycling of metabolites that are used by tumor cells to survive nutrient stress, hypoxia, and cytotoxic therapies .

Consequently, autophagy has emerged as a potential therapeutic target. However, such efforts are complicated by the growing realization that autophagy plays opposing roles in tumorigenesis, likely influenced by the stage of progression, driving oncogene and tissue type. Mouse models support a tumor-suppressive role for autophagy in the early stages of tumorigenesis by promoting genome stability and limiting necrosis and inflammation. Conversely, autophagy is required for malignant progression. Consistently, clinical studies have associated increased staining for the autophagy marker LC3 with melanoma metastases and with node positivity and decreased overall survival in human breast cancer, whereas overexpression of the key autophagy regulator Beclin1 is linked to reduced latency of melanoma metastasis.

Here, we report that autophagy is required for the motility and invasion of highly metastatic tumor cells due to a function for autophagy in promoting focal adhesion (FA) turnover. The key FA protein paxillin is degraded by autophagy, and paxillin is targeted to the autophagosome through the Src-regulated interaction of LC3 with a conserved LC3-interacting region (LIR) in paxillin. These results broaden our understanding of the multi-faceted role of autophagy in tumor progression and indicate that inhibiting autophagy may be an effective approach to blocking metastatic dissemination in the clinic.

HGP-Write: Testing Large Synthetic Genomes in Cells

Scientists want to synthesize the human genome. What does that mean?

Scientists Talk Privately About Creating a Synthetic Human Genome, nytimes, MAY 13, 2016.

Scientists met at Harvard University recently to discuss the fabrication of a human genome, meaning they would use chemicals to manufacture all the DNA contained in human chromosomes.

The project, called HGP-Write, is spurring both intrigue and concern in the scientific communities because it may become possible, such as through cloning, to use a synthetic genome to create human beings without biological parents.

Scientists Want To Synthesize The Human Genome. What Does That Mean?, newsy, May 15, 2016.

Image James King-Holmes/Science Source.

The Human Genome Project was aimed at reading the sequence of the three billion chemical letters in the DNA blueprint of human life. The new HGP-Write project would involve writing the human genome – synthesizing all the three billion units data from chemicals – and could have a big “scientific payoff“…

Greater consumption of fruits at young age significantly associated with a reduced risk of breast cancer

What teen girls should eat to reduce breast cancer risk

“This study underscores the importance of what a young girl eats for her future health. This study also has an important message for schools and the need to provide students with the opportunity to consume more fruits and vegetables as part of the school meal program.”

Maryam Farvid, research associate, Massachusetts General Hospital

Abstract

Objective
To evaluate the association between fruit and vegetable intake during adolescence and early adulthood and risk of breast cancer.

Design
Prospective cohort study.

Setting
Health professionals in the United States.

Participants
90 476 premenopausal women aged 27-44 from the Nurses’ Health Study II who completed a questionnaire on diet in 1991 as well as 44 223 of those women who completed a questionnaire about their diet during adolescence in 1998.

Main outcome measure
Incident cases of invasive breast cancer, identified through self report and confirmed by pathology report.

Fruit and vegetable consumption in adolescence and early adulthood and risk of breast cancer: population based cohort study, bmj, 11 May 2016.

Plate of Fruit image James P. Wells.

Results
There were 3235 cases of invasive breast cancer during follow-up to 2013. Of these, 1347 cases were among women who completed a questionnaire about their diet during adolescence (ages 13-18). Total fruit consumption during adolescence was associated with a lower risk of breast cancer. The hazard ratio was 0.75 (95% confidence interval 0.62 to 0.90; P=0.01 for trend) for the highest (median intake 2.9 servings/day) versus the lowest (median intake 0.5 serving/day) fifth of intake. The association for fruit intake during adolescence was independent of adult fruit intake. There was no association between risk and total fruit intake in early adulthood and total vegetable intake in either adolescence or early adulthood. Higher early adulthood intake of fruits and vegetables rich in α carotene was associated with lower risk of premenopausal breast cancer. The hazard ratio was 0.82 (0.70 to 0.96) for the highest fifth (median intake 0.5 serving/day) versus the lowest fifth (median intake 0.03 serving/day) intake. The association with adolescent fruit intake was stronger for both estrogen and progesterone receptor negative cancers than estrogen and progesterone receptor positive cancers (P=0.02 for heterogeneity). For individual fruits and vegetables, greater consumption of apple, banana, and grapes during adolescence and oranges and kale during early adulthood was significantly associated with a reduced risk of breast cancer. Fruit juice intake in adolescence or early adulthood was not associated with risk.

What Teen Girls Should Eat to Reduce Breast Cancer Risk, time, May 11, 2016.

Conclusion
There is an association between higher fruit intake and lower risk of breast cancer. Food choices during adolescence might be particularly important.