Search Results (37)

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. Full article

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. Full article

Purpose: To review parental pre-pregnancy and pregnancy exposures in relation to pediatric cancer (diagnosis before age 20). Methods: 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. Results: 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. Full article

Background/Objectives: Vaginal adenocarcinoma is a rare malignancy, accounting for less than 10% of all primary vaginal cancers. It predominantly affects older women but can also occur in younger populations, particularly in association with in utero diethylstilbestrol (DES) exposure. Given its rarity, evidence regarding the optimal management of vaginal adenocarcinoma remains limited. This review aimed to summarize the current understanding of vaginal adenocarcinoma, covering the epidemiology, etiology, diagnostic approaches, treatment modalities, prognosis, and areas requiring further investigation thereof. Methods: We conducted a search for the term “vaginal adenocarcinoma” in the PubMed, Scopus, and Web of Science databases from January 2016 to 28 April 2025. Results: Overall, 83 articles were included in the final review. Among them, 21 cases of vaginal adenocarcinoma were reported. Vaginal adenocarcinoma demonstrates a bimodal age distribution, with clear cell histology commonly linked to DES exposure and endometrioid or mucinous types seen in older patients. Risk factors include DES exposure, chronic inflammation, and human papillomavirus (HPV) infection. The diagnosis relies on a pelvic examination, imaging, and biopsy. Treatment typically involves surgery, radiotherapy, or a combination thereof, tailored to the stage and location, with chemotherapy reserved for advanced cases. The prognosis depends on the histologic subtype, tumor size, stage, and treatment response, with early-stage disease generally associated with better outcomes. Conclusions: Improved awareness of risk factors and early diagnostic strategies is critical to optimize patient outcomes. Research is needed to refine treatment protocols, explore targeted therapies and immunotherapy, and investigate the molecular underpinnings of vaginal adenocarcinoma, particularly non-DES-associated types. Full article

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. Full article

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. Full article

The male reproductive impairment caused by environmental estrogens (EEs) stands as a pivotal research area in environmental toxicology. Alpha2-macroglobulin (A2M) emerges as a promising molecule capable of counteracting oxidative stress induced by EEs. This study conducted exposure experiments spanning PND1 to PND56 employing ICR mice, aiming to delve into the expression patterns of A2M and its modulated IL-6 in the testicular tissue of mice subsequent to diethylstilbestrol (DES) and benzophenone (BP) exposure, while elucidating the pivotal role of ERs in this intricate process. Our findings revealed that upon DES exposure (10 and 100 nM), there was a pronounced upregulation of A2M (mRNA and in situ protein levels) in mouse testicular tissue. Similarly, exposure to BPs (BP-1, BP-2, and BP-3, each at 10 and 1000 nM) exhibited comparable effects and increasing A2M levels in serum. Notably, BP exposure also caused an elevation in IL-6 levels (which could be directly regulated by A2M) within testicular tissue (mRNA and in situ protein). Remarkably, the specific estrogen receptor antagonist ICI 182780 (0.5 mg/kg/day) was effective in reversing the upregulation of both A2M and IL-6 induced by BP exposure. Significantly, the results of theoretical prediction of the potential ERE site in the A2m gene promoter region and ChIP-qPCR experiment provide essential and strong evidence for the key conclusion that A2m is the target gene of ER. Taken together, our study highlights EEs’ ability to regulate A2M expression in the male reproductive system via the ER signaling pathway. This vital insight deepens our understanding of molecular mechanisms protecting against oxidative stress caused by EEs. Full article

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with any hormone action. They are categorized according to origin and use, such as industrial chemicals like polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs), plastics like bisphenol A (BPA), plasticizers like phthalates, pesticides like dichlorodiphenyltrichloroethane (DDT), fungicides like vinclozolin, and pharmaceuticals like diethylstilbestrol (DES). Natural EDCs, such as phytoestrogens, are present in the diet of both humans and animals. Polyphenols are a large group of natural compounds derived from plants and are found in beverages and food. They are grouped based on their chemical structure into flavonoids and nonflavonoids and are reported to have many beneficial effects on health, including, but not limited to, anticancer, antioxidant, and anti-inflammatory effects. Moreover, polyphenols have both pro- and antioxidant characteristics, and due to their antioxidant and anti-inflammatory potential, they presumably have a protective effect against damage induced by EDCs. However, polyphenols may act as EDCs. In this review, we report that polyphenols regulate the activity of EDCs, having both positive and negative effects. Hence, a better understanding of the associations between EDCs and polyphenols will allow the establishment of improved approaches to protect human health from EDCs. Full article

Background: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next (“third”) generation of offspring. Methods: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI. Results: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36–1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37–32.42). Based on mothers’ reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49–1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70–2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported. Conclusions: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed. Full article

Diagnostic of transsexualism and gender incongruence are terms to describe individuals whose self-identity does not match their sex assignment at birth. A transgender woman is an individual assigned male at birth (AMAB) on the basis of the external or internal genitalia who identifies and lives as a woman. In recent decades, a significant increase in the number of transgender people has been reported. Although, its etiology is unknown, biological, anatomical, genetic, environmental and cultural factors have been suggested to contribute to gender variation. In XY animals, it has been shown that environmental endocrine disruptors, through their anti-androgenic activity, induce a female identity. In this work, we described four XY individuals who were exposed in utero to the xenoestrogen diethylstilbesterol (DES) and were part of the French HHORAGES cohort. They all reported a female transgender identity starting from childhood and adolescence. This high prevalence of male to female transgenderism (1.58%) in our cohort of 253 DES sons suggests that exposure to chemicals with xenoestrogen activity during fetal life may affect the male sex identity and behavior. Full article

To characterize the hits from a phenotypic neurotoxicity screen, we obtained transcriptomics data for valinomycin, diethylstilbestrol, colchicine, rotenone, 1-methyl-4-phenylpyridinium (MPP), carbaryl and berberine (Ber). For all compounds, the concentration triggering neurite degeneration correlated with the onset of gene expression changes. The mechanistically diverse toxicants caused similar patterns of gene regulation: the responses were dominated by cell de-differentiation and a triggering of canonical stress response pathways driven by ATF4 and NRF2. To obtain more detailed and specific information on the modes-of-action, the effects on energy metabolism (respiration and glycolysis) were measured. Ber, rotenone and MPP inhibited the mitochondrial respiratory chain and they shared complex I as the target. This group of toxicants was further evaluated by metabolomics under experimental conditions that did not deplete ATP. Ber (204 changed metabolites) showed similar effects as MPP and rotenone. The overall metabolic situation was characterized by oxidative stress, an over-abundance of NADH (>1000% increase) and a re-routing of metabolism in order to dispose of the nitrogen resulting from increased amino acid turnover. This unique overall pattern led to the accumulation of metabolites known as biomarkers of neurodegeneration (saccharopine, aminoadipate and branched-chain ketoacids). These findings suggest that neurotoxicity of mitochondrial inhibitors may result from an ensemble of metabolic changes rather than from a simple ATP depletion. The combi-omics approach used here provided richer and more specific MoA data than the more common transcriptomics analysis alone. As Ber, a human drug and food supplement, mimicked closely the mode-of-action of known neurotoxicants, its potential hazard requires further investigation. Full article

The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a “hyper-inflammatory phenotype” and an increased hormone-dependent risk of UFs later in life. Full article

Estrogen receptor (ER)-positive breast cancer is the most common subtype, representing 70–75% of all breast cancers. Several ER-targeted drugs commonly used include the selective estrogen receptor modulator (SERM), tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Through different mechanisms of action, all three drug classes reduce estrogen receptor signaling. Inevitably, resistance occurs, resulting in disease progression. The counterintuitive action of estrogen to inhibit ER-positive breast cancer was first observed over 80 years ago. High-dose estrogen and diethylstilbestrol (DES) were used to treat metastatic breast cancer accompanied by harsh side effects until the approval of TAM in the 1970s. After the development of TAM, randomized trials comparing TAM to estrogen found similar or slightly inferior efficacy but much better tolerability. After decades of research, it was learned that estrogen induces tumor regression only after a period of long-term estrogen deprivation, and the mechanisms of tumor regression were described. Despite the long history of breast cancer treatment with estrogen, this therapeutic modality is now revitalized due to the development of novel estrogenic compounds with improved side effect profiles, newly discovered predictive biomarkers, the development of non-estrogen small molecules and new combination therapeutic approaches. Full article

With the widespread use of diethylstilbestrol (DES), it has become a common contaminant in the aquatic environment. It is toxic to a wide range of aquatic organisms, disrupting the water flea growth and further interfering with several ecosystem services. Nevertheless, the molecular mechanism of DES in water fleas is still unexplicit. In this study, the 21-day chronic test showed that a negative effect of growth and reproduction can be observed with DES exposure. Subsequently applied transcriptomic analysis illustrated the molecular mechanism in mode freshwater invertebrate Daphnia magna (D. magna) exposed to 2, 200, and 1000 μg·L⁻¹ of DES for 9 days. Meanwhile, exposure to DES at 200 and 1000 μg·L⁻¹ significantly restrains the growth (body length) and reproduction (first spawning time) of D. magna. Identified differentially expressed genes (DEGs) are majorly enriched relative to energy metabolism, lipid metabolism, the digestive system, transport and catabolism pathways which were remarkably changed. These repressed and up-regulated pathways, in relation to energy synthesis and metabolism, may be the reasons for the reduced body length and delayed first spawning time. Taken together, this study revealed that DES is a threat to D. magna in the aquatic environment and clarifies the molecular mechanism of the toxicity. Full article

Objective: Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause permanent adverse health effects in the exposed mothers, their children (exposed in utero), and also their grandchildren through germline contribution to the zygote. This study evaluated pregnancy duration and birthweight (BW) variations in the children and grandchildren born before, during, and after maternal DES treatment in the same informative families, to rule out genetic, endocrine, and environmental factors. Design and setting: Nationwide retrospective observational study on 529 families of DES-treated women registered at the HHORAGES-France Association. The inclusion criteria were: (i) women with at least three pregnancies and three viable children among whom the first was not exposed in utero to DES, followed by one or more children with fetal exposure to DES, and then by one or more children born after DES treatment; (ii) women with at least one pre-DES or post-DES grandchild and one DES grandchild; (iii) confirmed data on total DES dose. Women with severe pathologies or whose illness status, habitat, lifestyle habits, profession, treatment changed between pregnancies, and all mothers who reported pregnancy-related problems, were excluded. Results: In all, 74 women met all criteria. The preterm birth (PTB) rate was 2.7% in pre-DES, 14.9% in DES, and 10.8% in post-DES children (Cochran-Armitage test for trend, p = 0.0095). The mean BW was higher in DES than pre-DES full-term neonates (≥37 weeks of gestation) (p = 0.007). In grandchildren, BW was not different, whereas the PTB and low BW rates were slightly increased in children of DES women. Conclusions: These data within the same informative families show the DES impact on BW and PTB in DES and post-DES children and grandchildren. In particular, mean BW was higher in DES than pre-DES full-term neonates. This result may be in opposition to previous data from American cohorts, which reported lower BW in DES children, but is consistent with animal study. Our retrospective observational study highlights a multigenerational and likely transgenerational effect of this EDC in humans. Full article