X chromosome dosage compensation and sex-biased gene expression relashionship

Sex-Biased Expression of the Caenorhabditis elegans X Chromosome is a result of Both X Chromosome Copy Number and Sex-Specific Gene Regulation


Dosage compensation mechanisms equalize the level of X chromosome expression between sexes. Yet the X chromosome is often enriched for genes exhibiting sex-biased, i.e. imbalanced expression. The relationship between X chromosome dosage compensation and sex-biased gene expression remains largely unexplored. Most studies determine sex biased gene expression without distinguishing between contributions from X chromosome copy number (dose) and the animal’s sex.

Sex-Biased Expression of the Caenorhabditis elegans X Chromosome is a result of Both X Chromosome Copy Number and Sex-Specific Gene Regulation, Genetics, NCBI pubmed/27356611, 2016 Jun 29.

Here, we uncoupled X chromosome dose from sex-specific gene regulation in C. elegans to determine the effect of each on X expression. In early embryogenesis, when dosage compensation is not yet fully active, X chromosome dose drives the hermaphrodite-biased expression of many X-linked genes, including several genes that were shown to be responsible for hermaphrodite fate. A similar effect is seen in the C. elegans germline, where X chromosome dose contributes to higher hermaphrodite X expression, suggesting that lack of dosage compensation in the germline may have a role in supporting higher expression of X chromosomal genes with female-biased functions in the gonad. In the soma, dosage compensation effectively balances X expression between the sexes. As a result, somatic sex-biased expression is almost entirely due to sex-specific gene regulation. These results suggest that lack of dosage compensation in different tissues and developmental stages allow X chromosome copy number to contribute to sex-biased gene expression and function.

DES-related studies

Possible relationship between endocrine disrupting chemicals and hormone dependent gynecologic cancers

Approximately 800 chemicals are known or suspected to have the potential to function as EDC


The effects of the natural and synthetic estrogens have been studied for a long time but the data regarding estrogen related chemicals (endocrine disrupting chemicals, EDCs) and their effects on reproductive system are scarce. EDCs are hormone like agents that are readily present in the environment, which may alter the endocrine system of humans and animals.

Approximately 800 chemicals are known or suspected to have the potential to function as EDC.

Medical hypotheses, NCBI PubMed PMID: 27241264, 2016 Jul;92:84-7. doi: 10.1016/j.mehy.2016.04.041. Epub 2016 Apr 25

Expression of Estrogen by Libertas Academica.

Potential role of EDCs on reproductive disease has gained attention in medical literature in recent years. We hypothesize that exposure to low doses of EDCs in a chronic manner could cause hormone dependent genital cancers including ovarian and endometrial cancer. Long term exposure to low concentrations of EDCs may exert potentiation effect with each other and even with endogenous estrogens and could inhibit enzymes responsible for estrogen metabolism. Exposure time to these EDCs is essential as we have seen from Diethylstilbestrol experience. Dose-response curves of EDCs are also unpredictable. Hence mode of action of EDCs are more complex than previously thought. In the light of these controversies lower doses of EDCs in long term exposure is not harmless.

Possibility of this relationship and this hypothesis merit further investigation especially through in vivo studies that could better show the realistic environmental exposure. With the confirmation of our hypothesis, possible EDCs could be identified and eliminated from general use as a public health measure.

DES DiEthylStilbestrol Resources

Pesticide glyphosate disrupts uterine development

Neonatal exposure to a glyphosate based herbicide alters the development of the rat uterus

Glyphosate herbicide disrupts the development of the uterus of female rats when they are exposed for 7 days after birth.

A new study showed glyphosate caused cell proliferation and structural changes in the rats’ uterus, in spite of the fact that no signs of chronic or acute toxicity or differences in weight gain were seen in treated pups.

Glyphosate pesticide also disrupted the expression of proteins involved in uterine development.

The Argentine researchers conclude that glyphosate exposure may affect female fertility ; promote the development of uterine cancer.


Neonatal exposure to a glyphosate based herbicide alters the development of the rat uterus, Toxicology NCBI PubMed PMID: 27287056, 2016 Jun 7.

Roundup “probably causing cancer”  image by Global Justice Now.

Glyphosate-based herbicides (GBHs) are extensively used to control weeds on both cropland and non-cropland areas. No reports are available regarding the effects of GBHs exposure on uterine development.

We evaluated if neonatal exposure to a GBH affects uterine morphology, proliferation and expression of proteins that regulate uterine organogenetic differentiation in rats.

Female Wistar pups received saline solution (control, C) or a commercial formulation of glyphosate (GBH, 2mg/kg) by sc injection every 48h from postnatal day (PND) 1 to PND7. Rats were sacrificed on PND8 (neonatal period) and PND21 (prepubertal period) to evaluate acute and short-term effects, respectively.

The uterine morphology was evaluated in hematoxylin and eosin stained sections. The epithelial and stromal immunophenotypes were established by assessing the expression of luminal epithelial protein (cytokeratin 8; CK8), basal epithelial proteins (p63 and pan cytokeratin CK1, 5, 10 and 14); and vimentin by immunohistochemistry (IHC). To investigate changes on proteins that regulate uterine organogenetic differentiation we evaluated the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), Hoxa10 and Wnt7a by IHC.

  • The GBH-exposed uteri showed morphological changes, characterized by an increase in the incidence of luminal epithelial hyperplasia (LEH) and an increase in the stromal and myometrial thickness.
  • The epithelial cells showed a positive immunostaining for CK8, while the stromal cells for vimentin.
  • GBH treatment increased cell proliferation in the luminal and stromal compartment on PND8, without changes on PND21.
  • GBH treatment also altered the expression of proteins involved in uterine organogenetic differentiation. PR and Hoxa10 were deregulated both immediately and two weeks after the exposure. ERα was induced in the stromal compartment on PND8, and was downregulated in the luminal epithelial cells of gyphosate-exposed animals on PND21.
  • GBH treatment also increased the expression of Wnt7a in the stromal and glandular epithelial cells on PND21.

Glyphosate herbicide disrupts uterine development, gmwatch, 21 June 2016.

Neonatal exposure to GBH disrupts the postnatal uterine development at the neonatal and prepubertal period. All these changes may alter the functional differentiation of the uterus, affecting the female fertility and/or promoting the development of neoplasias.

Adverse health effects in children of women exposed in utero to diethylstilbestrol

2016 study results confirmed a transgenerational transmission of defects in male genital tract


Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women.

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES), US National Library of Medicine, NCBI pubmed/27203157, 2016 Feb 5.

Russian doll beauty and the beast, rawdonfox.

In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires.

There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary.

Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.

More DES DiEthylStilbestrol Resources

Prenatal exposure to DiEthylStilbestrol and sexual orientation in men and women

Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior



Both sexual orientation and sex-typical childhood behaviors, such as toy, playmate and activity preferences, show substantial sex differences, as well as substantial variability within each sex. In other species, behaviors that show sex differences are typically influenced by exposure to gonadal steroids, particularly testosterone and its metabolites, during early development (prenatally or neonatally). This article reviews the evidence regarding prenatal influences of gonadal steroids on human sexual orientation, as well as sex-typed childhood behaviors that predict subsequent sexual orientation. The evidence supports a role for prenatal testosterone exposure in the development of sex-typed interests in childhood, as well as in sexual orientation in later life, at least for some individuals. It appears, however, that other factors, in addition to hormones, play an important role in determining sexual orientation. These factors have not been well-characterized, but possibilities include direct genetic effects, and effects of maternal factors during pregnancy. Although a role for hormones during early development has been established, it also appears that there may be multiple pathways to a given sexual orientation outcome and some of these pathways may not involve hormones.


The possibility that exposure to ovarian hormones before birth influences sexual orientation in males also has been investigated. These studies have produced largely negative results. One study compared two groups of men exposed to the synthetic estrogen, DES, prenatally to matched controls. One group included 17 men exposed to DES alone and the second included 21 men exposed to DES along with natural progesterone. The study also included 10 men exposed prenatally to natural progesterone alone and 13 men exposed prenatally to synthetic progestins alone. Each of these groups was compared to matched controls. None of the four groups of hormone-exposed men differed from their respective controls in sexual orientation in fantasy or behavior. In addition, for all four samples combined, non-heterosexual orientation was reported by 8 of the 61 hormone-exposed men (13%), and by 8 of the 60 control men (13%). Two other research teams also have looked at sexual orientation in men exposed to DES prenatally, and have found no evidence of reduced heterosexual orientation. One studied 46 men exposed to DES and 29 unexposed controls. Men exposed to DES had somewhat more heterosexual coital experience than did controls, but did not differ in the number of heterosexual or homosexual coital partners. The second compared 1,342 DES-exposed men to 1,342 unexposed men, and found no difference in the numbers reporting sexual experience with a partner of the same sex, although, as noted above, this study used a relatively insensitive procedure for assessing sexual orientation. Nevertheless, the findings overall suggest that prenatal exposure to estrogen does not feminize sexual orientation in developing males, and this conclusion is consistent with predictions from results of experimental studies in other species, where early exposure of male animals to estrogen does not promote the development of female-typical behavior.

Prenatal exposure to DES and sexual orientation in women

One research team has studied three samples of women exposed prenatally to DES. The first sample included 30 women exposed to DES, 30 unexposed women recruited from the same gynaecological clinic and 12 unexposed sisters of the DES-exposed women. All of the participants had abnormal PAP smear findings. (Although DES rarely, if ever, causes genital virilization, prenatal exposure is often associated with abnormal PAP smears). Sexual orientation was assessed by interview and rated using Kinsey scale scores, and a global rating for lifelong sexual responsiveness (behavior and fantasy combined) was reported for 29 of the DES-exposed women and 30 of the controls. DES exposure was associated with reduced heterosexual orientation. Although 76% of the DES-exposed women were exclusively or almost exclusively heterosexual for lifetime scores, 24% were not. The comparable figure for the matched controls with abnormal PAP smear findings was 0%. The subset of 12 sister pairs showed a similar pattern with 42% of the DES-exposed sisters being not exclusively or almost exclusively heterosexual for their lifetime in terms of fantasy or behavior, compared to 8% of their unexposed sisters. Among the total group of DES-exposed women, five had experienced homosexual activities involving genital contact and two were living with a female partner. The same research team later reported data from this initial study along with data from two more samples of women exposed to DES prenatally. The first additional sample included 30 DES-exposed women, 30 demographically matched controls, with no history of DES-exposure or abnormal PAP smears, and 8 unexposed sisters. In this sample, a global Kinsey rating for lifelong sexual responsiveness was reported for 29 of the DES-exposed women and 30 of the matched controls. For the exposed group, 35% were not exclusively or almost exclusively heterosexual, whereas for the control group the comparable figure was 13%. Among the 20 sister pairs in the first and second samples, 40% of the DES-exposed group, compared to 5% of their sisters, were not exclusively or almost exclusively heterosexual. The second additional sample included 37 DES-exposed women whose mothers’ obstetrical files indicated prescription of at least 1000 mg of DES during the pregnancy, and age-matched daughters of women from the same obstetrical practice, whose mothers’ files showed that no DES was prescribed. For these women, 16% of the DES-exposed group and 5% of the unexposed group were not exclusively or almost exclusively heterosexual. For all three samples combined, 24% of the DES-exposed women, and 6% of the control women were not exclusively or almost exclusively heterosexual.

Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior, National Institutes of Health, Front Neuroendocrinol; 32(2): 170–182, NCBI PubMed PMC3296090, 2011 Apr

A separate investigation of women exposed to DES prenatally concluded that this exposure did not influence their sexual orientation. This study included 3,946 women exposed prenatally to DES and 1,740 women not exposed to DES. The DES-exposed women were somewhat less likely than the unexposed women to have had sex with a female partner. The DES-exposed women also were more likely than the unexposed women to have ever married, and for those who had had sexual intercourse with a man, were less likely to have had sexual intercourse before age 17 or to have had more than one sexual partner. These last differences raise questions about the comparability of the exposed and unexposed groups, and, although the large sample is impressive, the assessment of sexual orientation, in terms of a single question regarding sexual behavior, is relatively insensitive.

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Clear Cell Adenocarcinoma of the Ovary Associated with In Utero DES Exposure

A 45-year-old white woman was referred to an outpatient clinic with a self-discovered lump in the left lower abdominal quadrant


To our knowledge, this patient is the first clinical case featuring clear cell adenocarcinoma of the ovary that may be linked to diethylstilbestrol exposure in utero. We would like to emphasize that clear cell adenocarcinoma of the vagina and cervix, not the ovary, were previously shown to be sites for tumors in female offspring exposed prenatally to DES.

A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient’s mother received diethylstilbestrol therapy throughout the pregnancy. since clear cell cancers can develop, not infrequently, in foci of endometriosis, our patient’s pathology specimen was carefully inspected for endometriosis and none was found. Moreover, evidence linking prenatal DES exposure with chronic ovarian inflammation, paraovarian cysts, and high-grade squamous neoplastic proliferation in the genital tract has been accumulating. Although our patient is older than most patients in the Herbst cohort and a sporadic case of clear cell carcinoma cannot be excluded with certainty, all of the above changes were present in our patient’s pathology specimen. This further enhances our degree of suspicion on the causality between in utero DES exposure and the clear cell adenocarcinoma of the ovary in our patient.

Clear Cell Adenocarcinoma of the Ovary Associated With In Utero Diethylstilbestrol Exposure: Case Report and Clinical Overview, Medscape J Medv.11(1); 2009PMC2654676, 2009 Jan 7.

Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. Our case of probable DES-induced transplacental carcinogenesis more than 4 four decades after exposure reinforces the need for continued vigilance and routine gynecologic examinations in individuals prenatally exposed to this drug.

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Can clinical trials funding source be associated with favorable published outcomes?

Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov

image of casino-roulette
Medical science is being undermined when researchers do not publish all their findings, or are changing the things they are measuring after looking at the data… Matt Buck.


Through increased awareness of misreported outcomes, individual accountability, and feedback for specific journals, could we improve the quantity and quality of the medical data released to the general public?

Clinical trial registries are in widespread use to promote transparency around trials and their results.

To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes.

An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006.

ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999.

Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations.

Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization–funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization–funded trials without industry contributions (P = 0.005 across groups).

The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.

In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources.

Sources and more information
  • Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov, NCBI PMCID: PMC3374868, 2012 Jun 14.
  • How Scientists Are Doing A Bait-And-Switch With Medical Data, BuzzFeed, Jan. 22, 2016.
  • The COMPare (CEBM Outcome Monitoring Project) website and blog.

Removal of endocrine disrupting compounds from wastewater using polymer particles

Nanomaterials and UV light can “trap” chemicals for easy removal from soil and water

Nanoparticles that lose their stability upon irradiation with light have been designed to extract endocrine disruptors, pesticides, and other contaminants from water and soils. The system exploits the large surface-to-volume ratio of nanoparticles, while the photoinduced precipitation ensures nanomaterials are not released in the environment. MIT News.


Removal of endocrine disrupting compounds from wastewater using polymer particles, Water science and technology : a journal of the International Association on Water Pollution Research, NCBI PubMed PMID: 26744949, 2016.

This study evaluated the use of particles of molecularly imprinted and non-imprinted polymers (MIP and NIP) as a wastewater treatment method for endocrine disrupting compounds (EDCs).

MIP and NIP remove EDCs through adsorption and therefore do not result in the formation of partially degraded products. The results show that both MIP and NIP particles are effective for removal of EDCs, and NIP have the advantage of not being as compound-specific as the MIP and hence can remove a diverse range of compounds including 17-β-estradiol (E2), atrazine, bisphenol A, and diethylstilbestrol.

Removal of E2 from wastewater was also tested to determine the effectiveness of NIP in the presence of interfering substances and natural organic matter. Removal of E2 from wastewater samples was high and increased with increasing NIP. NIP represent an effective way of removing a wide variety of EDCs from wastewater.

The National DES Education Program: effectiveness of the California Health Provider Intervention

Academic detailing may increase physician knowledge and history taking practice

imahe of Health-Services provider
Men and Women who were exposed to DES are at higher risk for developing cancers compared to people who were not exposed to DES.

This 2002 research study explored the effectiveness of academic detailing on physician knowledge and practices related to preventative care for women exposed to synthetic estrogen (DES).

Physician participants were visited by a trained physician and received educational materials, management guidelines, chart reminders, medical history forms, office posters and brochures. They were informed about the reasons of why it was important to take a DES history. A lecture was featured to introduce the goals of this educational program to the participants. Physicians took a pre-intervention and post-intervention test that evaluated the change in their knowledge. To help assess study outcomes, patients likewise engaged in pre-intervention and post intervention surveys. While the study relied on self-reported outcome measures, the results revealed that academic detailing may increase physician knowledge and history taking practice.


Diethylstilbestrol (DES), a synthetic estrogen prescribed during pregnancy between 1938 and 1971, was later shown to have serious health effects, including higher risks of cancer in daughters and mothers. The authors report results of an intervention to increase health care providers’ awareness of preventive care for women exposed to DES before birth.

A controlled trial enrolled 20 to 25 health care providers in each of three communities to test the effectiveness of an academic detailing intervention. Outcomes (knowledge, routine screening) were assessed by provider questionnaires and patient surveys.

DES knowledge, familiarity with national guidelines, and screening for exposure increased significantly in the intervention communities but not in the control communities. The intervention effect for DES screening was significant (p = 0.01). Patient surveys confirmed provider self-report.

Academic detailing can increase DES knowledge and history taking among primary care providers. This intervention could be disseminated to increase knowledge of DES preventive care.

Sources and more information
  • The National DES Education Program: Effectiveness of the California Health Provider Intervention, American Board of Medical Specialties, 04/2002.
  • The National DES Education Program: effectiveness of the California Health Provider Intervention, Journal of cancer education: the official journal of the American Association for Cancer Education, NCBI PMID:12000106, 2002 Spring.
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2003 Recommendations for the Identification and Management of DES-Exposed Individuals

It is clear that DES has long-term effects that may develop over time

image of doctor-and-tablet
The health effects of DES exposure that may impact DES-exposed persons as they age are unknown; therefore, it is essential that health care providers continue to identify persons exposed to DES and continue to offer increased surveillance. Photo by NEC Corporation of America.


Diethylstilbestrol (DES) update: recommendations for the identification and management of DES-exposed individuals, Journal of midwifery women’s health, NCBI PMID: 12589302, 2003 Jan-Feb.

Diethylstilbestrol (DES) was etiologically linked to clear cell adenocarcinoma of the vagina in 1971.

This 2003 article reviews on-going research and emerging information relevant to DES-related health risks, thereby enabling women’s health care providers to maintain an evidence-based practice for their DES-exposed patients.

To accomplish these goals, the Center for Disease Control and Prevention (CDC) has initiated a national education campaign. This article describes the reasons for this new initiative, the target audiences, the DES historical framework (including major studies and findings), and populations that are affected. Clinical steps for the identification and management of the DES-exposed individual and resultant implications for midwifery and women’s health practices are reviewed.


  • Introduction
  • Adenocarcinoma and Cervical Cancer
  • Other Cancers
  • Anatomic Abnormalities
  • Pregnancy Outcomes
  • Effects of DES on Sons Exposed in Utero
  • Gynecologic Care for DES Mothers
  • Diagnostic Procedures Used to Assess Adenosis in DES Daughters
  • Preconception Care for Women Exposed to DES in Utero
  • Obstetric Care of Women Exposed to DES in Utero
  • Hormone Replacement Therapy
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