A ratiometric fluorescent paper-based sensor based on Fe/Eu-MOF for visual and sensitive detection of diethylstilbestrol.

Residues of 17β-estradiol (E2) and diethylstilbestrol (DES) in animal-derived foods pose significant reproductive and carcinogenic health risks. This study presents an innovative electrochemiluminescence (ECL) biosensing platform for the ultrasensitive and sequential detection of E2 and DES. The sensor features a robust interface constructed by immobilizing Ru(bpy)32+-doped ZnOx-incorporated zinc oxalate metal-organic framework (Ru@ZnOx), electrodeposited gold nanoparticles (Au NPs), and a thiolated capture probe onto an electrode. Crucially, a dual-amplification strategy coupled with switchable dual channels is designed. A CHA-DNAzyme system specifically amplifies the E2 signal, while an Exo Ⅲ-assisted system amplifies the DES signal. Both systems generate ferrocene-labeled signal probes, which quench the ECL emission of Ru@ZnOx upon hybridization with P DNA (signal-off mode). After E2 detection, the S1 probe is efficiently removed via strand displacement, enabling subsequent DES detection on the same sensor. In direct detection mode, it achieves wide linear ranges from 10- 6 to 10 ng mL-1 for both E2 and DES, with remarkably low detection limits (LOD) (S/N = 3) of 0.32 pg mL-1 for E2 and 0.56 pg mL-1 for DES. In the sequential mode for DES, the linear range is 10- 5 to 1 ng mL-1 with an LOD of 6.8 pg mL-1. The platform exhibits high stability, reproducibility, and specificity toward potential interferents, yielding excellent recoveries from 94.0% to 104.0% for determining E2 and DES in spiked milk samples. This work provides a highly reliable and sensitive method for monitoring trace levels of environmental estrogens, showcasing significant potential for ensuring the safety of animal-derived food products.

Subtle morphological and molecular responses to low-dose diethylstilbestrol in the developing rat penis.

Benzophenone-3 (BP-3), a widely used ultraviolet absorber in various scenarios, exhibits estrogenic toxicity at environmental concentrations—as demonstrated in our prior work. Given the importance of hepatic metabolism and the limitations of previous hepatotoxicity research (high-dose models, lack of mammalian data, etc.), we evaluated BP-3’s hepatic effects on postpartum mice at environmentally relevant levels. Postpartum mice were exposed to BP-3 via drinking water from postpartum day 1 (PPD1) to PPD35. Groups solvent control (0.001% DMSO), 10–1000 nM BP-3, and diethylstilbestrol (DES) were established. Basic growth performance, histopathological changes, and a range of molecular indicators were assessed. The results showed that BP-3 exposure induced dose-dependent increases in liver weight, histopathological alterations (sinusoidal dilation, hepatocyte edema, and necrosis), and significant upregulation of oxidative stress markers (Ros, Mda), chemokines (Ccl27a/b), and inflammatory factors (Tnf-α, Il-6, Nf-κb) at the mRNA level (all p < 0.05). Conversely, levels of antioxidant enzymes (Cat, Sod1/2) and anti-inflammatory factor Ho-1 were markedly decreased (p < 0.05). A clear dose-effect relationship was confirmed using the Integrated Biomarker Response (IBR) framework. This pioneering study establishes the hepatotoxicity of environmentally relevant BP-3 levels in mammals and offers methodological insights for endocrine disruptor assessment.

Hormone exposure in utero affects male- and female-typical behavior in animals, and these effects may persist in the next generation. Prenatal exposure to diethylstilbestrol (DES), a potent estrogen and endocrine disruptor, has been associated with a tendency toward greater heterosexual behavior in women, but the association in the next generation has not been studied. We evaluated the associations of maternal prenatal DES exposure with sexual behavior, sexual identity, and gender identity in 982 female offspring participating in the National Cancer Institute's DES Third Generation Study, a cohort born to mothers who were prenatally exposed and unexposed to DES. Odds ratio (OR) and 95% confidence intervals (CIs) were estimated from logistic regression models that included birth year. The ORs were 0.71 (CI 0.46-1.1) for DES in relation to non-heterosexual compared with heterosexual behavior, and 0.99 (CI 0.55-1.8) for non-heterosexual identity, compared with heterosexual identity. Results were similar after additional adjustment for education. Only three individuals reported a gender identity distinct from what was reported by the mother at cohort inception, preventing meaningful quantitative analysis of DES and gender identity. These data do not provide evidence of differences in sexual behavior and sexual identity in female offspring of mothers with and without prenatal exposure to DES.

Transcriptomic and physiological insights into Diethylstilbestrol toxicity in Phaeodactylum tricornutum.

Ultra-sensitive and rapid detection of diethylstilbestrol by constructing molecularly imprinted electrochemical sensor via hetero-interface engineering of Pt nanoparticles-decorated MXene/NH2-UiO-66.

Rationale:Primary vaginal adenocarcinoma (PVA) is an exceptionally rare malignancy, with most cases historically linked to in utero diethylstilbestrol (DES) exposure. Non–DES-associated PVA following definitive chemoradiotherapy for cervical cancer is extremely uncommon, and no standardized management protocol exists. This case illustrates a rare instance of radiation-associated PVA and highlights therapeutic considerations in previously irradiated pelvic fields.Patient concerns:A 53-year-old postmenopausal woman presented with intermittent vaginal bleeding occurring 5 years after radical hysterectomy and adjuvant chemoradiotherapy for stage IIA2 cervical squamous cell carcinoma.Diagnoses:Colposcopy-guided biopsies of the vaginal anterior wall revealed glandular architecture with cytological atypia. Immunohistochemistry demonstrated CK7(+), CK8/18(+), CEA(+), PAX8(−), ER(−), PR(−), p16 patchy weak negative, and wild-type p53. Systemic workup excluded metastatic disease, supporting the diagnosis of PVA (non–DES-associated, radiation-related).Interventions:In view of prior pelvic irradiation, the multidisciplinary team recommended dose-adjusted paclitaxel–cisplatin combination chemotherapy. Six cycles were administered, tailored to minimize cumulative toxicity.Outcomes:At 6-month follow-up, imaging studies confirmed complete clinical remission, with no locoregional recurrence or distant metastases.Lessons:This report underscores the potential for radiation-induced secondary vaginal adenocarcinoma in cervical cancer survivors, even after prolonged remission. Vigilant long-term surveillance, including annual vaginal cytology and targeted biopsies, is critical for early detection. Individualized therapeutic strategies – integrating prior treatment history, immunohistochemical profiling, and consideration of molecular alterations – are essential for optimizing outcomes in this rare patient population.

An efficient ECL aptasensor based on resonance energy transfer between NCDs@Ag3PO4 and Cu-doped Cu: Eu MOF for the detection of diethylstilbestrol.

Postnatal exposure to various benzophenones at environmentally relevant levels enhances the susceptibility of mammalian testes to cyclophosphamide-induced spermatogenic stress in adulthood.

Due to the growing environmental burden of endocrine-disrupting chemicals (EDCs), there is an increasing concern regarding the reproductive hazards posed by synthetic estrogens, particularly diethylstilbestrol (DES). However, the precise mechanisms by which DES disrupts uterine endocrine function and immune homeostasis leading to pregnancy failure remain unclear. Given that wild rodents serve as key reservoirs for zoonotic diseases such as plague, reproductive interventions targeting their pregnancy processes hold significant ecological implications for disease control. In this study, female mice in estrus were randomly divided into four experimental groups, receiving DES at doses of 0 (control), 0.02 (low), 0.2 (medium), and 2 mg/kg (high), respectively. For five consecutive days, mice were injected subcutaneously on a daily basis, with the goal of examining DES-related alterations in hormone secretion and local immune responses within the uterus and spleen. It was found that high-dose DES treatment significantly increased maternal body weight and spleen weight during early pregnancy (p < 0.05). Meanwhile, reproductive function declined progressively with increasing doses, as indicated by decreased ovarian and uterine weights, fewer embryos, and extended estrous cycle duration (p < 0.05). Hematoxylin and eosin staining revealed that high-dose DES markedly reduced uterine gland density at day P5, accompanied by epithelial vacuolar degeneration and nuclear pyknosis. The proportion of uterine glands relative to total uterine area also decreased significantly with increasing DES doses. Moreover, DES inhibited lymphocyte proliferation in both the uterus and spleen in a dose-dependent fashion, with ConA- and LPS-induced proliferation rates decreasing by 0.78–30.70% and 1.91–18.20%, respectively (p < 0.05). The proinflammatory cytokine IL-2 was significantly elevated by DES, whereas the anti-inflammatory cytokine IL-4 showed a notable decrease (p < 0.05). DES administration notably decreased uterine expression of proliferating cell nuclear antigen. In contrast, the numbers of B-cell lymphoma 2- and Bcl-2-associated X protein-positive cells rose, along with upregulated levels of inducible nitric oxide synthase. Furthermore, DES impaired antioxidant defenses in both the uterus and spleen, evidenced by the decreased activities of superoxide dismutase and glutathione peroxidase, reduced total antioxidant capacity, and elevated malondialdehyde levels. This study elucidates the multifaceted mechanisms by which DES impairs the early gestational reproductive environment, filling a critical knowledge gap regarding its interference with the uterus–immune axis, and expands the current understanding of the ecotoxicological impacts of endocrine-disrupting chemicals.

The environmental concentration of diethylstilbestrol and its structural analogues promote the conjugation transfer of ARGs through the pheromone effect.

Background and objectiveClear cell adenocarcinoma of the uterine cervix (CCAUC) is a rare malignancy, historically linked to in utero diethylstilbestrol (DES) exposure. However, several cases have been reported in non-DES-exposed populations, particularly in Asia. This study aimed to evaluate the clinicopathological features, treatment modalities, and outcomes in patients with CCAUC unassociated with DES exposure.MethodsWe conducted a retrospective analysis of 12 patients diagnosed with CCAUC between 2015 and 2022 at Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan. All diagnoses were confirmed by central pathology review. Patient data included demographics, clinical presentation, staging (FIGO: International Federation of Gynecology and Obstetrics), treatment details, and outcomes. Treatment approaches varied by disease stage and included surgery, chemotherapy, and concurrent chemoradiotherapy (CCRT).ResultsThe mean age at diagnosis was 46.25 years, with most patients being premenopausal. Tumor size exceeded 4 cm in 83.3% of cases, with 50% cases being either stage FIGO IIB or IIIA. A majority (91.7%) received CCRT. The five-year overall survival was 64.3%, and disease recurrence occurred in 25% of patients, with distant metastases being the most common.ConclusionsCCAUC in non-DES-exposed women tends to manifest in older age groups with bulky disease. Although treatment strategies are not standardized, primary surgery remains favorable for early-stage disease, while CCRT is appropriate for advanced stages. Given the rarity and poor prognosis of CCAUC, larger prospective studies are warranted to refine treatment guidelines and improve outcomes.

To review parental pre-pregnancy and pregnancy exposures in relation to pediatric cancer (diagnosis before age 20). We conducted literature searches using Ovid Medline and Scopus to find primary research studies, review articles, and meta-analyses published from 2014 to 17 March 2021. Strong evidence links increased risk of childhood cancer with maternal diabetes, age, and alcohol and coffee consumption during pregnancy. Both paternal and maternal cigarette smoking before and during pregnancy are associated with childhood cancers. Diethylstilbestrol (DES) exposure in utero has long been known to be causally associated with increased risk of vaginal/cervical cancers in adolescent girls. More recent evidence implicates in utero DES exposure to testicular cancer in young men and possible intergenerational effects on ovarian cancer in the granddaughters of women exposed to DES during pregnancy. There is strong evidence that childhood cancer risk is also associated with both high and very low birth weight and with gestational age. Evidence is also strong for the protective effects of maternal vitamin consumption and a healthy diet during pregnancy. Unlike early studies, those reviewed here show no association between in utero exposure to medical ionizing radiation, which may be explained by reductions over time in radiation doses, avoidance of radiation during pregnancy, and/or by inadequate statistical power to detect small increases in risk, rather than a lack of causal association. Evidence is mixed or conflicting for an association between childhood cancer and maternal obesity, birth order, cesarean/instrumental delivery, and prenatal exposure to diagnostic medical radiation. Evidence is weak or absent for associations between childhood cancer and multiple gestations or assisted reproductive therapies, as well as prenatal exposure to hormones other than DES, and medications.

Vaginal intraepithelial neoplasia (VaIN) and primary vaginal malignancies represent a rare subset of lower genital tract neoplasms, accounting for approximately 1% of all gynecological cancers. VaIN, a precursor lesion with substantial oncogenic potential, remains a diagnostic and therapeutic challenge. Its incidence is increasing due to heightened awareness, expanded cytologic and HPV screening, and routine colposcopic evaluation. Risk factors include prior cervical intraepithelial neoplasia, hysterectomy for CIN, immunosuppression, prior pelvic irradiation, persistent high-risk HPV infection, smoking, HIV, and diethylstilbestrol (DES) exposure. The vaginal microbiome's composition is increasingly recognized as a determinant of host susceptibility to HPV and neoplastic transformation. The Lower Anogenital Squamous Terminology (LAST) classifies VaIN into low-grade (VaIN 1) and high-grade squamous intraepithelial lesions (VaIN 2 and 3), with the latter harboring a significant risk of progression to invasive disease. High-grade VaIN necessitates definitive treatment, whereas low-grade lesions may be monitored. Therapeutic modalities include wide local excision, laser ablation, LEEP, and in select cases, upper vaginectomy. Non-excisional therapies such as CO₂ laser vaporization, photodynamic therapy, and plasma energy ablation are feasible in the absence of invasion. The choice of treatment should be individualized based on lesion extent, visualization, and prior therapies. Recurrence is not uncommon, warranting vigilant long-term surveillance. Primary vaginal carcinomas, chiefly squamous cell in origin, are staged clinically using FIGO and TNM classifications. Definitive management involves external beam radiotherapy (EBRT) with concurrent chemotherapy, followed by image-guided adaptive brachytherapy. Prognosis is primarily stage-dependent. Uncommon histologic subtypes such as vaginal melanoma and sarcomas pose unique diagnostic and therapeutic considerations due to their aggressive nature and rarity. This review consolidates the evolving landscape of VaIN and vaginal cancer, emphasizing diagnostic standardization, risk stratification, and a tailored multimodal treatment paradigm aligned with contemporary oncologic principles.

Abstract Introduction/Background: Diethylstilbestrol (DES), a synthetic estrogen and potent endocrine disruptor, was prescribed between the 1940s and 1970s to reduce risk of pregnancy complications and loss. DES was later found to be associated with increased risk of vaginal and other cancers among those who were prenatally exposed and is thus no longer prescribed during pregnancy. Whether in utero DES exposure is also associated with subsequent risk of developing benign breast disease (BBD), a risk factor for breast cancer, is unknown, and evaluating the impact of DES may serve as a model of potential intergenerational chemical toxicity. We assessed the risk of developing BBD, overall and by histologic BBD subtype, associated with prenatal DES exposure. Methods: From the National Cancer Institute Combined DES Cohorts Follow-Up Study, we examined associations of prenatal DES exposure with BBD risk among 4208 DES-exposed and 1830 unexposed women born between 1933 and 1976. Prenatal DES exposure status was abstracted from medical records or physician notes, and cumulative high or low DES dose was assigned in cohorts with recorded regional prescribing patterns. BBD diagnoses were self-reported on questionnaires from 1990 to 2017. Pathology-confirmation of BBD was available for 600 out of 1086 self-reported BBD cases. Cox proportional hazards models with age as the time scale were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the association of DES exposure (DES unexposed, exposed) with BBD risk. Follow-up started at birth and ended at the earliest of a diagnosis of BBD or breast cancer, death, or loss to follow up; the baseline hazard was stratified by year of birth (1933-1951, 1952-1953, 1954-1957, 1958-1976) and cohort, and further adjusted for baseline questionnaire year (1994, 1997 or 2001) and number of questionnaires a woman had answered in a time-varying fashion. We estimated cumulative incidence of BBD by DES exposure status. In additional analyses, we censored women with a BBD diagnosis only obtained by self-report at the age of BBD, and considered risk by histologic BBD subtype (nonproliferative, proliferative without atypia, proliferative with atypia) separately. To test for heterogeneity of associations of DES exposure by histologic BBD subtype, we used case-only polytomous logistic regression models adjusted for follow-up time and year of reported BBD. Results: 6038 women contributed a total of 333,455 person-years with a median follow-up of 43.0 (range: 13.8-74.0) years for cases (n=1086) and 59.9 (range: 19.7-80.3) years for non-cases (n=4952). BBD diagnoses were confirmed by pathology among 225/350 (64%) unexposed women and 375/736 (51%) DES-exposed women. For the 600 BBD cases with pathologic confirmation, histology did not vary meaningfully by DES exposure: 54.7% nonproliferative, 32.1% proliferative without atypia, and 9.5% proliferative with atypia. Comparing women who were prenatally exposed to DES to unexposed women, we found no evidence of an association between DES exposure and risk of BBD (aHR: 0.98; 95%CI: 0.85, 1.12). There was no evidence of a dose-response relationship or difference in cumulative incidence by exposure status. The aHRs for nonproliferative BBD, proliferative BBD without atypia, and proliferative BBD with atypia were 0.83 (95%CI: 0.64, 1.07), 0.94 (95%CI: 0.67, 1.32), and 0.60 (95%CI: 0.33, 1.09), respectively, with no evidence of statistical heterogeneity by BBD subtype (p-heterogeneity: 0.86). Conclusions: The risk of BBD was not elevated among women who were exposed to DES in utero, suggesting that previously observed increases in breast cancer risk associated with DES are not likely meditated through this pathological mechanism. Citation Format: Paloma R. Mitra, Kimberly A. Bertrand, Ruth M. Pfeiffer, Julie R. Palmer, Soumya Ramireddy, Marianne Hyer, William C. Strohsnitter, Kjersti Aagaard, Dezheng Huo, Elizabeth E. Hatch, Linda Titus, Rebecca Troisi, Gretchen L. Gierach. Prenatal diethylstilbestrol (DES) exposure and risk of benign breast disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-06-02.

In utero exposure to diethylstilbestrol (DES) is associated with increased risk of clear cell adenocarcinoma (CCAC) of the vagina or cervix. It is not clear whether these risks remain increased at older ages, and if the risks of other cancer sites, including breast cancer, are increased. This nationwide cohort study included 12,249 DES-exposed women and 2,070 unexposed sisters. Hormone-related risk factors and medical history were assessed through questionnaires, and cancer incidence through linkages with nationwide registries. Comparison with general population rates showed no difference in overall cancer risk (SIR = 0.98, 95%CI 0.93-1.04) or breast cancer risk (SIR = 1.03, 95%CI 0.96-1.11) for DES-exposed women. The rate of vaginal cancer was strongly increased for DES-exposed women (SIR = 10.5, 95%CI 5.72-17.6) and was increased in all age categories, including age 60-69 years (SIR = 8.3, 95%CI 1.00-29.9). Risks of both CCAC (SIR = 49.1, 95%CI 21.2-96.8) and squamous cell carcinoma (SCC; SIR = 5.86, 95%CI 2.15-12.8) of the vagina were significantly elevated. When comparing DES-exposed women with DES-unexposed sisters, overall cancer risk and risk of breast cancer were similar (HR = 0.93, 95%CI 0.78-1.11 and HR = 0.97, 95%CI 0.76-1.23, respectively). Apart from the established increased risk of vaginal cancer, women exposed to DES in utero do not seem to be at increased risk of cancer, including breast cancer. The risk of vaginal cancer remains increased also for women in their fifties/sixties. Moreover, the increased risk of vaginal cancer was seen for both subtypes CCAC and SCC. Screening for vaginal cancer up to higher ages than currently recommended (< 60 years) should be considered.

With industrial development, endocrine-disrupting chemicals have continued to accumulate in the environment, attracting growing attention due to their potential effects on biological health. The reproductive toxicity of diethylstilbestrol (DES), a synthetic estrogen widely present in the environment, is widely documented; however, studies on its effects on the immune system remain limited. In this study, adult male golden hamsters were subcutaneously administered varying doses of DES (0, 0.01, 0.1, and 1.0 mg/kg) for seven consecutive days to assess its immunomodulatory impact on peripheral blood and the spleen. We found that the DES treatment significantly reduced spleen index, white pulp area, and splenic lymphocyte proliferation while increasing caspase-3-positive apoptotic cells and inducible nitric oxide synthase expression. In peripheral blood, DES induced a dose-dependent suppression of lymphocyte proliferation, with lipopolysaccharide- and concanavalin A-stimulated proliferation reduced by 47.68-71.76% and 44.23-72.7%, respectively. Concurrently, DES significantly downregulated the pro-inflammatory cytokines IL-2 and IFN-γ (p < 0.01) while upregulating the anti-inflammatory cytokines IL-4 and IL-10 (p < 0.01). Furthermore, DES treatment impaired antioxidant defenses, decreasing the activity of superoxide dismutase, glutathione peroxidase, and catalase while elevating malondialdehyde levels. Notably, DES led to the upregulation of G protein-coupled estrogen receptor and estrogen receptor α at both transcriptional and protein levels, whereas estrogen receptor β mRNA expression increased despite a decline in protein levels. This study provides critical experimental evidence elucidating the immunoregulatory effects of endocrine-disrupting environmental estrogens.

Clear cell adenocarcinoma of the uterine cervix (CCAC) or vagina (CCAV) is rare and usually presents in postmenopausal women. Paediatric cases are rare, and have historically been associated with intrauterine exposure to diethylstilbestrol (DES). We aimed to summarise outcomes of CCAC and CCAV in children with no history of DES exposure. Systematic review of the Pubmed/Medline/Ovid databases from inception to 2024 according to PRISMA guidelines. The initial search identified 127 articles, and 29 articles were included in the final analysis. Forty-three cases of paediatric CCAC and CCAV were described. Median age at presentation was 10years [interquartile range (IQR): 8-14years]. Most patients presented with stage I tumours and symptoms of prolonged vaginal bleeding. Staging assessment included CT or MRI abdomen/pelvis and vaginoscopy with biopsy in most cases. Treatments consisted of variable combinations of chemotherapy, radiotherapy (external beam or brachytherapy) and surgery. Surgical procedures included localised resection only, radical trachelectomy or radical hysterectomy with pelvic lymph node clearance. Follow-up information was available for 88% patients and was overall very heterogeneous. Median duration of follow-up was 24months [IQR: 14-82.5]. There were seven reported deaths, and two additional patients experienced recurrence during follow-up. This is the first systematic review on the management and outcomes of children with CCAC and CCAV. The cases identified were few and heterogeneous, with limited information on longer term outcomes. Current evidence does not allow for the generation of paediatric-specific treatment guidelines. A cautious approach to the management of this rare and aggressive disease is essential, carefully balancing the desire of fertility preservation with the need for cure from disease.

Diethylstilbestrol (DES) is a synthetic non-steroidal estrogen, which was widely used to prevent preterm birth and abortion from the 1940s to the 1970s. DES can increase the incidence of infertility, the abnormal reproductive tract, and autoimmune diseases. However, the mechanism underlying DES on early pregnancy in mice is unclear. This study evaluated the effects of DES on early pregnancy in mice, especially on uterine receptivity and decidualization. Newborn female mice were subcutaneously injected with 0.1 mg/kg DES, 1 mg/kg DES, or sesame oil as controls for 5 consecutive days. At 6 weeks old, these female mice were mated with 8-12-week-old fertile males to obtain pregnancy. The uteri of these mice were collected on days 4, 5, and 8 of pregnancy for further analysis. On days 5 and 8 of pregnancy, the number of implantation sites in 0.1 mg/kg DES group is similar to the control group, while almost no implantation sites are detected in the 1 mg/kg DES group. On day 4 of pregnancy, there was no significant difference in uterine receptive molecules between the control group and the 0.1 mg/kg DES group. However, the levels of uterine receptive molecules in the 1 mg/kg DES group are abnormal. In addition, 6 μM DES significantly inhibits mouse in vitro decidualization. The excessive activation of pyroptosis may lead to pregnancy failure. The pyroptosis-related molecules in the 1 mg/kg DES group were significantly up-regulated, suggesting that DES may contribute to pregnancy failure by over-activating pyroptosis.