Diethylstilbesterol Research Articles

Modulation of tyrosine receptor imposed by Estrogen in Memory and Cognition in Female Rats.

The present study aimed to investigate the potential role of estrogen in modulating the pathogenesis of dementia-type-AD phenotype, possibly by tyrosine kinase. Female Wistar rats were ovariectomized (OVX) and were treated with Diethylstilbesterol (DES), an estrogen analogue (20μg/kg/day, i.m.), and Imatinib, a tyrosine kinase inhibitor (30mg/kg/day, orally), for two months. Animals underwent surgical ovariectomy exhibited significant memory deficits in spatial memory assessment as mean dwell time, short-term memory as spontaneous alteration, and novel object recognition after a chronic period of 4 weeks. OVX animals administered with DES produced significant restoration of memory dysfunction in comparison to OVX, as exhibited by Morris water maze (p=0.0003), Y maze (p<0.0001), and NORT. Imatinib prior to DES treatment in OVX animals showed significant decline in memory functions, which confirms the potential involvement of tyrosine receptor kinase activity in improved memory functions offered by estrogen. Levels of estradiol were significantly (p<0.0001) lower in the OVX group compared to normal which was significantly (p<0.0001) restored in the OVX+E group. Biochemical estimations of TBARS, glutathione, and acetylcholinesterase levels in the brain showed a significant increase in oxidative stress among the OVX group. However, a significant restoration of oxidative changes with TBARS (p=0.0496), glutathione (p<0.0001), and acetylcholinesterase activity (p=0.0201) of OVX animals receiving DES was observed in comparison to animals receiving imatinib followed by DES. These implications in the brain signify that estrogen and tyrosine kinase play an important role in the pathogenesis of dementia. In conclusion, estrogen offers neurochemical mediation for cognition and memory possibly via modulation of tyrosine kinase signaling in female subjects.

Dysmorphic Uterus: More Questions than Answers.

A T-shaped uterus is a rare uterine malformation that is classically associated with diethylstilbesterol (DES) exposure. Surprisingly, the prevalence of T- and Y-shaped uterus has increased in recent years despite the absence of a diagnostic consensus and a correlation with the reproductive outcomes has been observed. A systematic electronic database search for all English-language studies published on reproductive outcomes associated with dysmorphic uteri over the past 10 years using PubMed, Google Scholar, and Scopus was performed. This uterine malformation is associated with impaired reproductive outcomes, including primary infertility, miscarriage, ectopic pregnancy, and preterm birth. Hysteroscopic metroplasty is a simple surgical procedure that could potentially improve outcomes in subfertile women, but the data are not robust. Studies reported significant improvements in implantation and pregnancy rates after corrective metroplasty in women undergoing in vitro fertilization. However, multicenter, prospective, randomized, and controlled trials are needed to validate these findings and to help define clear diagnostic criteria, surgical indications, and appropriate follow-up of reproductive outcomes after the procedure.

Systematic Omission of Pregnant and Lactating Women from Malignant Haematology Trials Perpetuates a Cycle of Exclusion, Data Shortage and Disadvantage

Background: Pregnant or breastfeeding women are routinely excluded from clinical trials due to fear of teratogenicity and toxicity of therapeutic agents, despite a paucity of evidence to support this practice. In response to the diethylstilbesterol (DES) and thalidomide-induced embryopathy in the mid-20 th century, the US Food and Drug Administration (FDA) released new regulations excluding Women of Child-Bearing Potential (WoCBP) from phase I and II trial participation, followed by an introduction of a new pregnancy category labelling system in 1979. The legacy of these measures is a reliance on accidental exposure pregnancy data rather than rigorous clinical trial efficacy and safety data for medication use in pregnancy and lactation.WoCBP when enrolled in clinical trials are often subjected to prescriptive contraceptive requirements to mitigate the risk of accidental pregnancy, without informed consent for the contraceptive side effects. These barriers to trial participation for WoCBP, particularly in the setting of life-threatening haematological diseases, prevent timely access to therapies only accessible via clinical trial participation. Lymphoma and leukaemia in pregnancy occur with an approximate incidence of 1 in 6000 and 1 in 75,000-100,000 pregnancies respectively. We examined the rates and rationale for exclusion of these patients from clinical trials, as well as contraceptive requirements for WoCBP.Methods: We conducted a cross-sectional observational study of clinical trial protocols recruiting patients with potentially life-threatening haematological malignancies. We searched the clinicaltrials.gov clinical trials database for trial protocols enrolling acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Hodgkin lymphoma (HL) and/or Diffuse Large B Cell lymphoma (DLBCL) between January 2016 and January 2021. Studies were included if they included WoCBP (15-55 years of age). Studies without complete electronic protocol access were excluded. The following data was collected: target disease, study phase, study location, age of patients, whether pregnant or lactating women were excluded (rationale if provided including evidence of teratogenicity), type of contraception and duration mandated and presence or absence of informed consent for contraception.Results: We identified 68 trials for AML, ALL, DLBCL and HL (40%, 26%, 21% and 13% respectively) (Table 1). Most were phase I-II studies (91%) of novel agents (90%) and of note, the majority were of non-chemotherapy agents (83%). The majority (97%) excluded pregnant women and (69%) without providing rationale. Only 2% cited evidence for embryopathy in either human or animal studies. Most studies (84%) explicitly excluded lactating women, of which 85% did not provide justification. Contraception was mandatory in 90% of the protocols, with 47% of these requiring at least two different forms of contraception for the entire study period. These included hormone-based contraception, barrier methods and abstinence. None of the protocols provided informed consent for the potential side effects of the mandated contraceptive methods in the context of the study.Conclusion: The theoretical harm from anti-cancer therapy to the foetus is typically given greater moral precedence than is a pregnant woman's autonomy. Pregnant and lactating women were almost universally excluded from the trials in this study with limited rationale provided. Study protocols frequently mandated contraception without informed consent of its associated risks in the context of the study. This perpetuates the lack of efficacy and safety data in this patient population, and drives a cycle of systematic exclusion, data shortage, and inequity.Pregnant and lactating women with life threatening haematological malignancies with no alternative treatment options should be eligible for clinical trials where this offers potentially life-saving therapy, with appropriate informed consent around the indefinable and potentially harmful effects on their foetus. We propose obligatory rationale for exclusion of pregnant and breastfeeding women in all clinical trials, using safety data from either human or animal studies and contraception informed consent. [Display omitted] DisclosuresHamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Primary clear cell adenocarcinoma of the vagina in a young female with uterus didelphys

Adenocarcinomas of clear cell type are uncommon tumors accounting for 5-10% of all vaginal tumours which in turn account for approximately 2% of all gynaecologic malignancies. Though Clear cell Adenocarcinomas arising in the setting of previous Di-Ethyl–Stilbesterol [DES] exposure have been reported quite often, only few cases of these not associated with DES have been documented. Amongst non-DES exposed patients, CCAs are said to be sporadic or in association with endometriosis in women of peri/postmenopausal age or in association with some congenital genitourinary anomalies mostly affecting young females. A 16 year old female presented with heavy bleeding per vaginum since 2 months. On per vaginal examination a polypoidal mass was felt on posterior wall of vagina. Ultrasonography revealed the presence of a uterus didelphys in addition to this mass. Polypectomy was done. On microscopy, a diagnosis of clear cell adenocarcinoma was made which was confirmed on immunohistochemistry. There was no history of any DES exposure in the mother. We present here a case of an adolescent female with uterus didelphys and no DES exposure who was diagnosed as a case of Vaginal Clear cell Adenocarcinoma. The rarity of this tumour among DES-exposed cases and its presence in non-exposed patients warrants a more thorough search for the underlying pathology.

Determination of in vivo estrogenic potential of Di-isobutyl phthalate (DIBP) and Di-isononyl phthalate (DINP) in rats.

Estrogenic potential of Di-isobutyl phthalate (DIBP) and Di-isononyl phthalate (DINP) was studied using two different test systems. Two different doses of DIBP (250 and 1250 mg/kg) and DINP (276 and 1380 mg/kg) were administered to immature female rats (20 days old) orally once daily for 3 and 20 days in uterotrophic and pubertal assay, respectively. The animals were sacrificed on day 4 and day 41 in case of 3-day uterotrophic and 20-day pubertal assay, respectively. The results indicated that non-significant alterations in uterine and ovarian wet weight were observed in both the DIBP- and DINP-treated groups while the uterus weight increased significantly (i.e., 4-6 times) in the Diethylstilbesterol (DES)-treated group in both the assays. In the present study, precocious vaginal opening occurred at 26 days of age in the DES-treated group with a mean body weight of 30.39 ± 1.08 g. However, no precocious vaginal opening was found in any of the DIBP- and DINP-treated groups. The results indicated that both the phthalate compounds were unable to induce elevation in the uterine weight in both the assays and unable to cause vaginal opening indicating non-estrogenic potential of both the phthalate compounds, i.e., DIBP and DINP in vivo.

A Review on Drug Disaster in the History of Medicine

A drug is, in the broadest of terms, chemical substance that has known biological effects on humans or other animals. In pharmacology, drug is a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. Drugs may be used for limited duration, or on regular basis for chronic disorders. Drug disaster may be defined as the ill effect/hazards it causes or it may cause after it reaches the market for the patients. This article presents broad review of drug disaster in the history of medicine. This becomes major problem since it is observed after the routine and detailed research and clinical studies. In this review, eight drug disaster cases was studied and the criteria for the study being drug category, use, disaster, manufacture and incidents. The drugs involved in this disaster studies are Sulfanilamide, Diethyl stilbesterol, Rofecoxib, Thalidomide, Fenfluramine/Phenteramine, Cerivastatin, Troglitazone and Nimesulide. From the different cases we reviewed, all were either due to the incomplete and thorough clinical studies of the active pharmaceutical ingredient and the excipients as whole or due to the inadequate post marketing surveillance of the specified product.

Abstract 3192: The environmental estrogen bisphenol A (BPA) regulates mammary gland stem cells

Abstract A study by the Centers for Disease Control revealed detectable levels of the environmental toxin Bisphenol A (BPA) in urine samples from over 92% of people in the NHANES (National Health and Nutrition Examination Survey) study. BPA is a small molecule used in the polymerization of polycarbonate plastics. These plastics are widely used in food containers, water bottles, dental fillings and toys, among many other products. BPA is similar to the synthetic estrogen diethylstilbesterol (DES) and can bind to estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ). Because BPA is lipophilic and has been detected in mammary gland fat in humans, we hypothesize that BPA is an estrogen mimic in the stromal adipocytes in the breast and can induce stem cell proliferation and survival, leading to breast tumor formation. Indeed, BPA increases the size and number of mammospheres from normal mouse mammary gland and from human MCF7 breast cancer cells. Adipocytes co-cultured with mammospheres increased the size of the spheres, and BPA further increased the size of adipocyte co-cultured mammospheres. BPA upregulates the stem cell markers Nanog, OCT4 and SOX2 in mammospheres. ERα and pCREB were shown to bind to an enhancer downstream of the SOX2 gene after BPA treatment. Finally, BPA increased the size of tumor xenografts in NUDE mice. Together these experiments demonstrate that BPA may induce breast cancer via ERα and pCREB regulation of breast cancer stem cells. Citation Format: Cydney Nichols, Xiangming Ding, Gustavo Miranda-Carboni, Susan Amy Krum. The environmental estrogen bisphenol A (BPA) regulates mammary gland stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3192. doi:10.1158/1538-7445.AM2014-3192

Potential Carcinogens from Steroid Hormones and Diethyl Stilbesterol (DES): Chemical Relationships between Breast, Ovarian and Prostate Cancers

With the exception of certain environmental causes of cancer like sun and occupational exposure (asbestos), many malignancies result from smoking, alcohol or dietary factors and others may be due to endogenous factors. While a large amount of research has focused on exogenous carcinogens both environmental and dietary, much less has been devoted to potential endogenous cancer initiators. In part, this stems from disbelief that naturallyoccurring compounds in man are carcinogens. Yet, reactive metabolites of the steroid hormones and related compounds have the potential to transform cellular nucleic acids and thereby initiate precursors to the malignant cell. An example is a potential metabolite of estradiol, which could lead to catechol estrogens, was shown to be as mutagenic as 3-methylcholantrene in 1980. And yet, no further research has been done to determine whether this proposed metabolite occurs in mammalian systems and if it does, whether it is a causative agent in breast or ovarian malignancies. Four important questions are: (1) if such metabolites arise in vivo, will tests show them to be carcinogenic?, (2) is there a dose-response relationship, in their causation of malignancies?, (3) what are the biological mechanisms, by which these compounds arise?, and (4) are these pathways perturbed in breast and prostate cancer patients, leading to excessive accumulation of these mutagens? These are merely four of many questions that must be addressed when examining potential endogenous carcinogens. Increasingly, there appears to be a genetic relationship between breast, ovarian and prostate cancers. Could that connection arise from chemical similarities between carcinogenic initiators derived from steroid hormones, their formation, incorporation into nuclear receptors as well as their rate of hydrolysis? These issues in addition to a clarification of the origin of such endogenous carcinogens will be explored. A testable hypothesis is proposed.

Early exposure of 17α‐ethynylestradiol and diethylstilbestrol induces morphological changes and alters ovarian steroidogenic pathway enzyme gene expression in catfish, Clarias gariepinus

Environmental estrogens are major cause of endocrine disruption in vertebrates, including aquatic organisms. Teleosts are valuable and popular models for studying the effects of endocrine disrupting chemicals (EDCs) in the environment. In the present study, we investigated the changes caused by exposure to the synthetic estrogens 17α-ethynylestradiol (EE2 ) and diethylstilbesterol (DES) during early stages of growth and sex differentiation of air-breathing catfish, Clarias gariepinus, at the morphological, histological, and molecular levels. Catfish hatchlings, 0 day post hatch (dph) were exposed continuously to sublethal doses of EE2 (50 ng/L) and DES (10 ng/L) until 50 dph and subsequently monitored for ovarian structural changes and alteration in the gene expression of steroidogenic enzymes till adulthood. Treated fish exhibited morphological deformities such as spinal curvature, stunted growth, and yolk-sac fluid retention. In addition to ovarian atrophy, DES-treated fish showed either rudimentary or malformed ovaries. Detailed histological studies revealed precocious oocyte development as well as follicular atresia. Further, transcript levels of various steroidogenic enzyme and transcription factor genes were altered in response to EE2 and DES. Activity of the rate-limiting enzyme of estrogen biosynthesis, aromatase, in the ovary as well as the brain of treated fish was in accordance with transcript level changes. These developmental and molecular effects imparted by EE2 and DES during early life stages of catfish could demonstrate the deleterious effects of estrogen exposure and provide reliable markers for estrogenic EDCs exposure in the environment.

Awash in Urine: DES and Premarin® in Multispecies Response-ability

Awash in Urine: DES and Premarin® in Multispecies Response-ability Donna Haraway Cyborg Littermates Cyborgs are kin, whelped in the litter of post–World War II information technologies and globalized digital bodies, politics, and cultures of human and not-human sorts. Cyborgs are not machines in just any sense, nor are they machine-organism hybrids. In fact, they are not hybrids at all. They are, rather, imploded entities, dense material semiotic “things”—articulated string figures of ontologically heterogeneous, historically situated, materially rich, virally proliferating relatings of particular sorts, not all the time everywhere, but here, there, and in between, with consequences. Particular sorts of historically situated machines signaled by the words “information” and “system” play their part in cyborg living and dying. Particular sorts of historically situated organisms, signaled by the idioms of labor systems, energetics, and communication, play their part. Finally, particular sorts of historically situated human beings, becoming-with the practices and artifacts of technoscience, play their part. Characterized by partial connections, the parts do not add up to any whole; but they do add up to worlds of nonoptional, stratified, webbed, and unfinished living and dying, appearing and disappearing. Cyborgs are constitutively full of multiscalar, multitemporal, multimaterial critters of both living and nonliving persuasions. Cyborgs matter in terran worlding. But cyborgs are critters in a queer litter, not the Chief Figure of Our Times. “Queer” here means not committed to reproduction of kind and having bumptious relations with futurities. Irreducible to cyborgs, the litter interests me, the particular kin and kind nursed on the fluid and [End Page 301] solid effluvia of terra in the late twentieth and early twenty-first centuries. I write this brief essay in gratitude to the people of WSQ and especially to the authors of the three essays in this Viral issue who play with “my” cyborg in order to relay the string figures—the speculative fabulations, the scientific facts, the science fictions, and the speculative feminisms—to whatever sorts of tentacular grippers will receive the pattern to keep living and dying well possible in “our times.” Made up of an aging California dog, pregnant mares on the western Canadian prairies, human women who came to be known as “DES daughters,” lots of menopausal U.S. women, and assorted other players in the story of “synthetic” and “natural” estrogens, the litter for this essay is decanted from bodies awash in a particular pungent fluid—urine. Waste and resource, out-of-place urine from particular female bodies is the salty ocean needed for my tale. Leaks and eddies are everywhere. These leaks and eddies might help open passages for a praxis of care and response—response-ability—in ongoing multispecies worlding on a wounded terra. DES for Hot Peppers In October 2011 my twelve-year-old canine friend and lifelong sports partner, Cayenne, aka Hot Pepper, started taking a notorious, industrially produced, nonsteroidal, synthetic estrogen called DES (diethylstilbesterol) to deal with urinary leakage (“Diethylstilbestrol,” n.d.).1 Perhaps I should not write she “started taking,” but rather, “I started feeding her as an occasional late-night treat, following her last pee, a luscious, slippery, Earth Balance® margarine-coated capsule of DES.” Plato gave us all the tones in the extricable ambiguities of his pharmakon: cure and poison; care, curare; remedy, toxin. Aging spayed bitches like Cayenne and postmenopausal women like me often could use a hormonal tightening of slack smooth muscles in the urethra to keep socially unacceptable leaks plugged up. The term “estrogen deficiency” is a tough one for feminists like me, marinated at a young age in the women’s health movements and feminist science studies, to pronounce. But the fact is that a few extra dabs of estrogens do some handy jobs in aging mammalian female bodies—at a price, of course, in many currencies of living and dying. Granted, the adrenal glands still secrete some estrogens for those of us with missing or dried-up ovaries, but output is pretty low and smooth muscle can get pretty flaccid. But giving this beloved, elder, nonreproducing dog to whom I am [End Page 302] responsible even very low dose and infrequent diethylstilbesterol caused acute DES anxiety syndrome in me. My blood...

Diallyl Sulfide inhibits Diethystilbestrol induced Breast Tumor in Female ACI rats

Previous studies in this lab have shown that diallyl sulfide (DAS) inhibits DNA adduct formation, lipid peroxidation and modulate detoxification and DNA repair genes and enzymes in breast tissue of diethylstilbesterol (DES) treated female ACI rats. These findings are important since estrogen and estrogenic compounds such as DES have been shown to induce breast cancer in humans and animals. In addition, scientists have postulated that DAS, a constituent of garlic, is an effective cancer prevention agent. In this study, we hypothesize that the release of inteleukin 6 by DES induced cancerous cells leads to activation of the JAK‐ Stat pathway which can increase cell proliferation and inhibit apoptosis. DAS may modulate these changes. To prove this hypothesis, 6 week old female ACI rats were implanted with Control (silicon implant alone) and DES (50mg/kg) silicon pellets were implanted s.c. In addition, these animals were fed normal chow or DAS (as co‐treatment) containing chow ad libitum for six months. At sacrifice, representative mammary tissueand all palpable mammary tumors were removed for genetic and histopathologicalanalysis. Genetic analysis was done by microarray analysis and validated using PCR array. Our data show significant increase in interleukin 6 gene expression in cancerous cells (DES group) and a significant decrease in the DAS co‐treatment group. Furthermore, a significant modulation of genes associated with the JAK/STAT pathway was observed. Animals co‐treated with DAS were free of tumor. For the first time our lab was able to show that DAS prevents DES induced breast tumors in female ACI rats.Funded by RCMI Grant #2G12RR03020‐24

Diethylstilbesterol has Gender-Specific Effects on Weight Gain and Bone Development in Mice

Neonatal exposure to diethylstilbesterol (DES) in female mice programs estrogen-sensitive tissues, resulting in greater body weight gain and positive effects on bone architecture at adulthood. Using the CD-1 mouse model, the objective of the present study was to examine how short-term neonatal exposure to DES modulates weight gain as well as bone mineral density (BMD), bone strength, and bone microarchitecture in both males and females at adulthood. Male and female offspring (n = 8–12 pups/treatment/gender) were randomized to DES (2 mg/kg bw/d) or control (corn oil) from postnatal day 1 to 5 (subcutaneous injection, once daily) and sacrificed at 4 mo of age. Body weight was measured weekly, while bone mineral, strength, and microarchitecture were measured at 4 mo of age. DES treatment resulted in significantly higher body weight in females but lower weight in males at 4 mo of age. In DES-treated females, markedly higher BMD of lumbar vertebrae (LV1–LV3) was translated into significantly stronger LV2 that was more resistant to fracture; similar effects were observed at the femur midpoint. At the spine, males had a markedly lower BMD and peak load, suggesting an adverse effect. Microstructural analyses demonstrated that functional changes in femurs, i.e., peak load, were primarily due to modulation of cortical bone. In conclusion, neonatal exposure to DES exerted gender-specific effects on body weight gain and bone health.

Activation of Penile Proadipogenic Peroxisome Proliferator‐Activated Receptor γ with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development

Exposure to the estrogen receptor alpha (ERα) ligand diethylstilbesterol (DES) between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ERα and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Transcripts for PPARs α, β, and γ and γ1a splice variant were detected in Sprague-Dawley normal rat penis with PPARγ predominating. In addition, PPARγ1b and PPARγ2 were newly induced by DES. The PPARγ transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPARγ protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ERα and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPARγ expression. These results suggest a biological overlap between PPARγ and ERα and highlight a mechanism for endocrine disruption.

DEVELOPMENTAL EXPOSURE TO XENOBIOTIC ESTROGENS PERMANENTLY PROGRAMS EXPRESSION OF EXTRACELLULAR MATRIX AND ADHESION MOLECULES IN A MOUSE ENDOMETRIOSIS MODEL

Estrogens have permanent developmental effects in the fetus. Our lab is investigating the potential for xenobiotic estrogens to program endometriosis-related genes during fetal development. It has recently been reported that women exposed in utero to the synthetic estrogen diethylstilbesterol (DES) had an 80% increased incidence of endometriosis, an estrogen dependent disease characterized by the growth of ectopic endometrium. Additionally fraternal twins, who are exposed to 60–80% increased levels of circulating estrogens in utero, have a 70% increased incidence of endometriosis. We therefore hypothesized that developmental estrogen exposure would result in the exacerbation of endometriosis in adulthood in a mouse model of surgically-induced endometriosis. In a preliminary study we found that developmental DES exposure resulted in 55% larger endometriotic lesions in adulthood. To investigate mechanisms that led to the exacerbation of endometriosis we examined the ability of developmental DES to alter proliferation and program extracellular matrix and adhesion molecule gene expression in endometriotic lesions. Methods: Pregnant female mice were given a daily oral dose of 0.1 microg/kg DES or vehicle control on gestation days 11–17. When mice exposed in utero reached adulthood, endometriosis was surgically induced by autotransplantation of uterine tissue to the intestinal mesentery. After 4 weeks, mice were euthanized and eutopic and ectopic endometrium were collected. Results: Proliferation was significantly greater in endometriotic lesions from DES developmentally treated mice compared to control treated mice as detected by immunolocalization of the nuclear proliferation marker Ki67. To examine potential developmental programming of adult gene expression, an extracellular matrix and adhesion molecule pathway specific microarray was used. Overall, 19% (21 out of 113) of extracellular matrix and adhesion molecule genes were up-regulated and only 3% (3 out of 113) were down-regulated in endometriotic lesions from developmentally DES exposed mice compared to control treated mice. Upregulated genes included several procollagens, integrins, laminins, matrix metallopeptidase 12, fibronectin, and periostin. Downregulated genes included synaptotagmin 1, thrombospondin 1, and tissue inhibitor of metalloproteinase 4. These results indicate that developmental xenoestrogen exposure may program the fetus and result in a more favorable environment for the growth of ectopic endometriotic lesions by increasing the expression of genes for extracellular matrix and adhesion molecules that are necessary for tissue re-modeling and endometriotic lesion growth. (platform)

Accounting for Risk Disparity: An Alternative to Market Share Liability

Market share liability emerged as a response to the problematic diethylstilbesterol (DES) litigation of the 1980s, during which plaintiff daughters were unable to identify the specific defendants responsible for their injuries. California was the first state to devise a market share liability system for apportioning damages among DES producers. Adopting a variation of the underlying policy of Summers v. Tice, the Supreme Court of California in Sindell v. Abbott Laboratories held that, as between a negligent defendant and an innocent plaintiff, the former should bear the costs of injury notwithstanding lingering tortfeasor identification issues. Several state courts have adopted components of the Sindell framework. Plaintiffs advancing market share liability theories beyond the DES context have largely failed. Market share liability has been rejected in litigation involving asbestos, cigarettes, breast implants, benzene, and toxic chemicals. Courts have typically held that substances of diverse variety, such as asbestos, fail the Sindell fungibility requirement, while finished products like cigarettes are easily identified by brand and do not create the tortfeasor identification problem posed by the DES market. A significant exception to this trend is the limited application of market share liability to Factor VIII blood products. Factor VIII is a protein that occurs naturally in human blood and regulates clotting and coagulation. Commercial Factor VIII was formerly acquired from private blood donors and then fractionalized to remove plasma. It was then processed and supplied to hemophiliacs to prevent uncontrollable bleeding. During the 1980s, numerous Factor VIII products became contaminated by the human immunodeficiency virus (HIV). Similar to the DES cases, plaintiffs suffering injury through contaminated Factor VIII are often unable to identify the specific manufacturer(s) responsible for their harm. Extended latency periods between exposure and knowledge of injury are also common. Additionally, like DES, HIV contamination is often detected long after a Factor VIII user has contracted the virus. This Note advocates an alternative to market share liability for fungible products that produce disparate consumer risks by using the Factor VIII litigation as a starting point. Part II highlights the distinctions between DES as a uniformly toxic substance producing a net reduction in social utility and products such as Factor VIII, which create positive or negative utility based on the care exercised by particular defendants during the production process. Part III examines the market-based inefficiencies that are likely to result from applying market share liability to products like Factor VIII. Part IV proposes an alternative model for apportioning liability among a class of defendants responsible for producing functionally interchangeable goods that generate dissimilar levels of consumer risk. The model advanced herein seeks to ensure full victim compensation while creating incentives for firms to reduce product risks. This will be achieved by a three-phase system for assigning damages. Phase 1 will permit defendants to exculpate themselves from the lawsuit by disproving causation. Phase 2 will replace the national market used by market share liability regimes with a sub-market representing the relative culpability of the non-exculpated defendants. Phase 3 will modify the sub-market liability apportionment by awarding damage discounts to those defendants that have effectively reduced product risks without qualifying for full exculpation.

Comparison of enzyme‐linked immunosorbent assay with liquid chromatography–tandem mass spectrometry for the determination of diethylstilbesterol residues in chicken and liver tissues

A competitive enzyme-linked immunosorbent assay (ELISA) was developed for the quantitative detection of the diethylstilbesterol (DES). Polyclonal rabbit antisera, raised against protein conjugate diethylstilbesterol-mono-caroxyl-propyl-ethyl-bovine-serum-albumin (DES-MCPE-BSA), were utilized in immobilized antibody-based and competitive immunoassays. Assay conditions, including concentrations of antisera and horseradish peroxidase, (HRP)-DES, were optimized. The effects of incubation time, surfactant concentration, ionic strength and pH of the medium were also investigated. The typical calibration curve gave an average IC(50) value of 2.4 ng/mL, calibration range from 0.2 to 30.5 ng/mL and a detection limit of 0.07 ng/mL. The specificity of the assay was tested against DES structurally related compounds, and the assay proved highly selective for DES. Assay performance was validated using spiked chicken meat and liver tissue samples. Moreover, it was compared with liquid chromatography-tandem mass spectrometry. The ion pair for quantification of DES was m/z 267.4/251.4, and the linear equation of DES was y = 0.1033x + 0.0126 (r = 0.9960). The two analytical methods can be applied to monitor DES and other steroid residues in foods.

Primary mucinous adenocarcinoma of the vagina: Possibility of differentiating from metastatic adenocarcinomas

Primary vaginal adenocarcinomas are rare neoplasms. Herein is reported a case of primary vaginal mucinous adenocarcinoma with an interesting mucin profile, presumably arising from a lesion of adenosis in a patient without in utero exposure to diethylstilbesterol (DES). The patient, a 44-year-old woman, had undergone vaginal total hysterectomy 10 years previously for myoma uteri corporis. The histological features of the vaginal intramural tumor found in this patient resembled those of mucinous adenocarcinoma of the endocervical type. Therefore, it was necessary to determine whether or not the tumor was metastatic from an occult cervical adenocarcinoma. However, the adenocarcinoma cells of the present case did not contain sulfomucin at all, being different from most mucinous adenocarcinoma cells of the endocervical type. Moreover, there were foci of adenosis adjacent to the adenocarcinoma foci, which also did not contain sulfomucin. These findings indicate that the mucinous adenocarcinoma arose from vaginal adenosis. Further studies are necessary to investigate whether lack of sulfomucin expression is a characteristic feature of vaginal adenosis.

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer

Hsp90 is a chaperone for over 100 'client proteins' in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Neonatally Administered &lt;I&gt;tert&lt;/I&gt;-Octylphenol Affects Onset of Puberty and Reproductive Development in Female Rats

There now is evidence that many of the synthetic chemicals released into the environment can impact on the function of the endocrine system of many organisms. One group of chemicals, the alkylphenols, used in paints, pesticides, herbicides, detergents, and plastics, has been found to have the ability to bind estrogen receptors. This estrogenic property makes these compounds potentially hazardous to the developing reproductive system and neuroendocrine brain. In this study we deter- mined the effects of exposure to the environmental toxins 4-nonylphenol (NP) and 4-tert-octylphenol (OP) and to synthetic estrogen diethylstilbesterol (DES) during the early postnatal period (d 0-10) on the development of reproductive function. The day of vaginal opening, ovulation, prepubertal LH levels, LH response to estradiol, estrous cyclicity, and ovarian histology were determined. In the OP- and DES-treated groups, the vaginal opening was observed to have occurred several days prior to that of the control group. The NP-treated group showed vaginal opening at ages similar to those of the control group. Treatment with OP prevented ovulation in a significant number of animals, as well as in all animals treated with DES, whereas the control and NP-treated animals ovulated normally. Animals treated with DES and OP had significantly lower ovarian weights and higher uterine weights than either control animals or NP-treated animals. Higher basal LH levels, as well as the absence of the prepubertal LH surge, were observed in both DES- and OP-treated animals. A significant number of OP-treated animals showed no LH response to the estradiol-17beta challenge. NP-treated animals responded positively to the estradiol-17beta challenge. Persistent estrus was also apparent in both OP- and DES-treated animals. Upon histological examination, the ovaries in OP-treated animals were found to have a decreased number of corpora lutea and an increased number of preantral and atretic follicles. These data suggest that exposure to OP during the critical period of sexual brain differentiation affects the onset of puberty and reproductive development.

内分泌撹乱化学物質のマクロファージ機能に及ぼす影響

In previous papers we reported that endocrine disrupters (EDs) such as diethyl stilbesterol (DES), 4,4'-isopropylidene diphenol (Bisphenol A: BPA), bis (2-ethylhexyl) phthalate (EHP) and p-nonylphenol (NP) stimulated proliferative responses and cytokine productions of murine spleen cells and thymus cells in vitro. In this paper we report the effect of EDs on murine macrophage functions in vitro. DES, BPA, EHP and NP stimulated thioglycolate-induced peritoneal exudate cells (macrophages) to produce cytokines such as interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor and macrophage chemotactic protein- 1. The effect of these EDs was observed at the concentrations of 10(-6)-10(-8) M, and the maximum response was obtained at 10(-7 M.) The accessory function for T cell activation and CD86 expression, an important molecule for accessory function, was enhanced in EDs-treated macrophages. These results suggest that EDs have modulating activities of macrophage functions.