The key role of androgen in male sex maintenance

Blockage of androgen and administration of estrogen induce transdifferentiation of testis into ovary

2017 Study Abstract

Induction of sex reversal of XY fish has been restricted to the sex undifferentiated period.

In the present study, differentiated XY tilapia were treated with trilostane (TR), metopirone (MN) and glycyrrhetinic acid (GA) (inhibitor of 3β-HSD, Cyp11b2 and 11β-HSD, respectively) alone or in combination with 17β-estradiol (E2) from 30 to 90 dah (days after hatching). At 180 dah, E2 alone resulted in 8.3%, and TR, MN and GA alone resulted in no secondary sex reversal (SSR), whereas TR + E2, MN + E2 and GA + E2 resulted in 88.3, 60.0 and 46.7% of SSR, respectively.

This sex reversal could be rescued by simultaneous administration of 11-ketotestosterone (11-KT). Compared with the control XY fish, decreased serum 11-KT and increased E2 level were detected in SSR fish. Immunohistochemistry analyses revealed that Cyp19a1a, Cyp11b2 and Dmrt1 were expressed in the gonads of GA + E2, MN + E2 and TR + E2 SSR XY fish at 90 dah, but only Cyp19a1a was expressed at 180 dah. When the treatment was applied from 60 to 120 dah, TR + E2 resulted in 3.3% of SSR, MN + E2 and GA + E2 resulted in no SSR.

These results demonstrated that once 11-KT was synthesized, it could antagonize E2-induced male-to-female SSR, which could be abolished by simultaneous treatment with the inhibitor of steroidogenic enzymes. The upper the enzyme was located in the steroidogenic pathway, the higher SSR rate was achieved when it was inhibited as some of the precursors, such as androstenedione, testosterone and 5α-dihydrotestosterone, could act as androgens. These results highlight the key role of androgen in male sex maintenance.

Image credit Rusty Clark.

Perinatal Exposure to DES Increases the Susceptibility to Develop Mammary Gland Lesions after Estrogen Replacement Therapy

Hormones and Cancer, April 2017, Volume 8, Issue 2, pp 78–89

2017 Study Abstract

The development of the mammary gland is a hormone-regulated event.

Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation.

Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer.

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats, US National Library of Medicine National Institutes of Health, Hormones and Cancer, April 2017, Volume 8, Issue 2, pp 78–89, NCBI PubMed PMID: 28078498, 2017 Apr 8.

Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland.

Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months.

Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals.

ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells.

Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR.

Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone.

In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

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Emerging, priority contaminants with endocrine active potentials in sediments, fish from the River Po, Italy

High levels of endocrine-disrupting chemicals found in sediments and fish from the Italian River Po and its Lambro tributary

Researchers have recommended that fish from some sections of the River Po and the River Lambro, one of the Italian River Po tributaries, should not be eaten due to high levels of some endocrine-disrupting chemicals in the river sediments and fish. This recommendation is based on an extensive update regarding pollution levels of such substances in the rivers.

Abstract

There is a substantial lack of information on most priority pollutants, related contamination trends, and (eco)toxicological risks for the major Italian watercourse, the River Po. Targeting substances of various uses and origins, this study provides the first systematic data for the River Po on a wide set of priority and emerging chemicals, all characterized by endocrine-active potentials.

Flame retardants, natural and synthetic hormones, surfactants, personal care products, legacy pollutants, and other chemicals have been investigated in sediments from the River Po and its tributary, the River Lambro, as well as in four fish species from the final section of the main river. With few exceptions, all chemicals investigated could be tracked in the sediments of the main Italian river for tens or hundreds of kilometres downstream from the Lambro tributary.

Nevertheless, the results indicate that most of these contaminants, i.e., TBBPA, TCBPA, TBBPA-bis, DBDPE, HBCD, BPA, OP, TCS, TCC, AHTN, HHCB, and DDT, individually pose a negligible risk to the River Po. In contrast, PBDE, PCB, natural and synthetic estrogens, and to a much lower extent NP, were found at levels of concern either to aquatic life or human health. Adverse biological effects and prohibition of fish consumption deserve research attention and management initiatives, also considering the transport of contaminated sediments to transitional and coastal environments of the Italian river.

More Information
  • Emerging and priority contaminants with endocrine active potentials in sediments and fish from the River Po (Italy), US National Library of Medicine National Institutes of Health, Environmental science and pollution research international, NCBI PubMed PMID: 25956513, 2015 Sep.
  • High levels of endocrine-disrupting chemicals found in sediments and fish from the Italian River Po and its Lambro tributary, Science for Environment Policy, January 2016.
  • Fishing Po image credit Edizonn.

What does Estrogen do?

Why is estrogen important and what can go wrong with estrogen levels?

Perinatal carcinogenesis: growing a node for epidemiology, risk management

Childhood Cancers, Toxicology and Applied Pharmacology, 2004

Abstract

Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here.

There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention.

Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies, Toxicology and applied pharmacology, NCBI PubMed PMID: 15313581, 2004 Sep.

Image via alexsarmy.

With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors.

Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions.

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Critical windows of exposure for children’s health and agents related to childhood cancer

The carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis

Abstract

In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal.

Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive.

Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models, Environ Health Perspectives, NCBI PubMed PMID: 10852857, 2000 Jun.

Image via alexsarmy.

In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.

DIETHYLSTILBESTROL EXPOSURE

Unlike the situation for preconceptional exposures, there is good evidence that exposure of the human fetus to certain potentially harmful agents can increase the risk of cancer during childhood and possibly during early adulthood. Nonetheless, although numerous potentially harmful agents are suspected including infections, drugs, and maternal lifestyle characteristics the only two generally accepted carcinogenic in utero exposures are ionizing radiation and DES: the former acting directly on the fetus and the latter acting via the placenta.

The strong associations for DES have led researchers to postulate in utero effects for other endogenous and exogenous hormones, particularly for cancers with a suspected hormonal component to their etiology such as breast and testicular cancers. Further, since the birth of the first test-tube baby in 1978 there has been concern about the health of offspring resulting from assisted reproductive technology (ART). Multiple pregnancies often result from ART, which is one of the main determinants of the health of the child at birth. The importance of follow-up studies of these children to assess adverse health outcomes diagnosed after birth, even in adulthood, has been recognized, but few comprehensive and powerful epidemiological studies have been done. Two case reports have highlighted possible increases in cancer incidence in children born as a result of in vitro fertilization, raising concerns about the role of prenatal exposure (before and after conception) to high levels of estrogen and related compounds used for ovarian stimulation. To date, there are limited epidemiological data on this topic; a study of U.K. births after ART failed to find an excess incidence of childhood cancer, but, as noted by the authors, the study was too small to be able to detect a reasonable excess, even if it existed.

With respect to mechanisms and the timing of exposure, it is thought that the carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis. This has been documented for DES, which causes various genital tract abnormalities in males as well as in females. In addition, it has been suggested that the exposure of pregnant women to substances that inhibit the function of the topoisomerase II enzymes could be related to the development of acute leukemia in their offspring.

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Estrogenic activity of water, sediment, and fish bile of the Pearl River, Southern China

Evaluation of estrogenic activity in the Pearl River by using effect-directed analysis

Abstract

This study investigated estrogenic activity of water, sediment, and fish bile of the Pearl River in southern China by effect-directed analysis based on in vitro yeast screen assay and chemical analysis.

Results showed higher estradiol equivalents (EEQ) for surface water in dry season than in wet season. Simple risk assessment suggested that high estrogenic risk would be expected in Shima River and Danshui River receiving discharge of effluents from cities in the region. Fractionation and effect-directed analysis showed that estrogenic activity mainly occurred in relatively polar fractions of surface water.

Evaluation of estrogenic activity in the Pearl River by using effect-directed analysis, Environmental science and pollution research international, NCBI PubMed PMID: 27522204, 2016 Nov.

Pearl River by toyohara.

Seven target estrogenic compounds

  1. bisphenol A,
  2. 4-nonylphenol,
  3. 4-tert-octylphenol,
  4. 17α-ethynyl estradiol,
  5. estrone,
  6. diethylstilbestrol,
  7. and 17β-estradiol

only accounted for part of the measured estrogenic activity, with the rest contributions from other potential estrogenic chemicals such as phenols.

Findings from this study suggest that fish in the river could be affected by those estrogenic chemicals. Proper measures should be taken to reduce the estrogenic activity in wastewaters before they are discharged into the riverine system in order to protect aquatic organisms.

Transgender Men Can Face Fighting Breast Cancer Too

The medical world has blind spots in its understanding of how to take care of trans men and women

A transgender man, is somebody who is born female, and then takes male hormones to change gender. Many transgender people switch gender without having surgery to change their body.

… ” Zil Goldstein, a nurse practitioner and program director at Mount Sinai’s transgender center, said that while she had concerns about the long-term safety of transgender hormones, she worried more about the possible harm from not prescribing them – researchers report that 41 percent of transgender people attempt suicide.” …

…  “trans men with breast cancer were often urged to stop taking testosterone. One reason is that the body converts some testosterone to estrogen, which can speed the growth of many breast tumors. And some breast cancers may also be stimulated by testosterone, … “

Endocrine disrupting chemicals and uterine fibroids

Endocrine disruptors and reproductive disorders

Abstract

Uterine fibroids are the most frequent gynecologic tumor, affecting 70% to 80% of women over their lifetime.

Although these tumors are benign, they can cause significant morbidity and may require invasive treatments such as myomectomy and hysterectomy.

Many risk factors for these tumors have been identified, including environmental exposures to endocrine-disrupting chemicals (EDCs) such as genistein and diethylstilbestrol.

Endocrine disrupting chemicals and uterine fibroids, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 967–977, September 15, 2016.

“Feeling ill” image Maria Morri.

Uterine development may be a particularly sensitive window to environmental exposures, as some perinatal EDC exposures have been shown to increase tumorigenesis in both rodent models and human epidemiologic studies.

The mechanisms by which EDC exposures may increase tumorigenesis are still being elucidated, but epigenetic reprogramming of the developing uterus is an emerging hypothesis.

Given the remarkably high incidence of uterine fibroids and their significant impact on women’s health, understanding more about how prenatal exposures to EDCs (and other environmental agents) may increase fibroid risk could be key to developing prevention and treatment strategies in the future.

DES DiEthylStilbestrol Resources

Endocrine disrupting chemicals and endometriosis

Endocrine disruptors and reproductive disorders

Abstract

Endometriosis is an estrogen dependent gynecologic disease with lasting implications for many women’s fertility, somatic health, and overall quality of life.

Growing evidence suggests that endocrine disrupting chemicals (EDCs) may be etiologically involved in the development and severity of disease.

We weigh the available human evidence focusing on EDCs and endometriosis, restricting to research that has individually quantified chemical concentrations for women, included a comparison group of unaffected women, and used multivariable analytic techniques.

Endocrine disrupting chemicals and endometriosis, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 959–966, September 15, 2016.

laparoscopic surgery for endometriosis: fuschia_foot.

Evidence supporting an environmental etiology for endometriosis includes metals/trace elements, dioxins, and other persistent organic pollutants, as well as nonpersistent chemicals, such as benzophenones and phthalates.

To address the equivocal findings for various EDCs, future research directions for filling data gaps include

  1. use of integrated clinical and population sampling frameworks allowing for incorporation of new diagnostic modalities;
  2. the collection of various biologic media, including target tissues for quantifying exposures;
  3. study designs that offer various comparison groups to assess potentially shared etiologies with other gynecologic disorders;
  4. and novel laboratory and statistical approaches that fully explore all measured EDCs for the assessment of mixtures and low dose effects and the use of directed acyclic graphs, and supporting causal analysis for empirically delineating relationships between EDCs and endometriosis.