Fetal Origin of Adult Disease

Abstract from “Environmental Exposures and Adverse Pregnancy Outcomes: A Review of the Science”

During the last two decades, chronic disease has replaced infectious disease as the major focus of public health concern. The top 4 leading causes of death in the United States are chronic diseases. There remains much unknown about the etiology of many chronic conditions, which in most cases is probably multifactorial. Studies from the 1990s found that effects on the fetal environment, such as through poor or inadequate nutrition, can result in an increased risk of adult onset of chronic conditions, such as coronary heart disease. This has been called the fetal origins hypothesis (also known as the Barker theory), which proposes that external influences on the fetal environment can increase the risk of later disease in adulthood.

Diethylstilbestrol (DES)—a synthetic estrogen given to US women between 1938 and 1971 to prevent pregnancy complications illustrates the fetal origins of later in life disease. In utero DES exposure left mature female offspring at increased risk of clear cell adenocarcinoma of the vagina and cervix, breast cancer, structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models, which have also predicted changes later found in DES-exposed humans, such as increased incidence of uterine fibroids, oviductal malformations, and second generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES granddaughters and increased hypospadias in DES grandsons.

Diethylstilbestrol shows the adverse effects of fetal exposures to synthetic chemicals may not be apparent at birth or even for many years afterward, and that continued monitoring of this cohort of exposed children and grandchildren is necessary to inform potential effects of prenatal exposures to other contaminants.

Reference. Image credit Hush Naidoo.

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Less plastic use help decrease harmful chemicals in the body

The ReThink Plastic Pilot Study Community Report, 2018

A new pilot study has shown that women who reduce their exposure to plastic see a decrease in estrogen-mimicking chemicals in their bodies within a month.

The chemicals used in the manufacture of many plastics are known to mimic estrogen activity. There is strong scientific evidence linking these “environmental estrogens” to breast cancer. The ReThink Plastic study was designed to reduce exposure to these chemicals using simple, practical behavior change and to build a coalition of plastic use reduction by spreading the study messages. This approach could result in broad benefits by effectively reducing exposure to harmful chemicals in plastic and thus protecting against breast cancer and protecting the environment against plastic pollution.

Specifically, the objectives of the study were to:

  1. Inform participants about the harmful effects of chemicals that are in plastic
  2. Teach participants simple ways to reduce the use of plastic in order to reduce the potential for harmful health effects
  3. Ask participants to spread the message to other friends and family
  4. Evaluate the effectiveness of the study:
    • Examine changes in “plastic use” behavior before and after the study
    • Examine changes in estrogenic activity before and after the study in a small sub-study of post-menopausal women.

Reference.

Staying with the Trouble : Making Kin in the Chthulucene

Donna J. Haraway’s poetic guide to finding connection in a time of crisis, 2016

Description

In the midst of spiraling ecological devastation, multispecies feminist theorist Donna J. Haraway offers provocative new ways to reconfigure our relations to the earth and all its inhabitants. She eschews referring to our current epoch as the Anthropocene, preferring to conceptualize it as what she calls the Chthulucene, as it more aptly and fully describes our epoch as one in which the human and nonhuman are inextricably linked in tentacular practices. The Chthulucene, Haraway explains, requires sym-poiesis, or making-with, rather than auto-poiesis, or self-making. Learning to stay with the trouble of living and dying together on a damaged earth will prove more conducive to the kind of thinking that would provide the means to building more livable futures. Theoretically and methodologically driven by the signifier SF—string figures, science fact, science fiction, speculative feminism, speculative fabulation, so far—Staying with the Trouble further cements Haraway’s reputation as one of the most daring and original thinkers of our time.

Awash in Urine,” chapter 5, begins with personal and intimate relations, luxuriating in the consequences of following estrogens that connect an aging woman and her elder dog, specifically, me and my companion and research associate Cayenne. Before the threads of the string figure have been tracked far, remembering their cyborg littermates, woman and dog find themselves in histories of veterinary research, Big Pharma, horse farming for estrogen, zoos, DES feminist activism, interrelated animal rights and women’s health actions, and much more. Intensely inhabiting specific bodies and places as the means to cultivate the capacity to respond to worldly urgencies with each other is the core theme.

More Information

  • Introduction and customer reviews on amazon and goodreads.
  • Donna Haraway lectures at the San Francisco Art Institute, April 25, 2017.
  • Chapter 5 Awash in Urine DES and Premarin in Multispecies Response-ability is lightly revised from Women’s Studies Quarterly 40, nos. 3/4 (spring/summer 2012): 301 – 16.
DES DiEthylStilbestrol Resources

Sex Hormones and Related Compounds, Including Hormonal Contraceptives

ResearchGate, Side Effects of Drugs Annual, July 2017

Abstract

This is a review of publications from January 2016 to December 2016 on sex hormones and related compounds. This chapter covers estrogens (diethylstilbestrol, estradiol and derivatives), progestins (drospirenone, levonorgestrel, medroxyprogesterone, ulipristal), hormone replacement therapy (combination estrogen and progestin, estrogen only, tibolone, oral preparations and topical preparations), hormonal contraceptives (oral, non-oral, combination and progestin only), in vitro fertilization agents, triptorelin (gonadotropin-releasing hormone agonist), anastrozole (aromatase inhibitor) testosterone, anabolic steroids and androgen deprivation therapy.

Request the full-text on ResearchGate.

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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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