Chronic bisphenol A induced neurotoxicity: Exposure risk, molecular fate within carp and its potential phytoremediation.

Bisphenol A (BPA) is an endocrine-disrupting toxicant commonly used in the plastics industry, as a result, it is present in large quantities in the environment. Therefore, current study was designed to assess BPA induced neurotoxicity and molecular fate within common carp (Cyprinus carpio), largely used edible fish. Following 6 weeks exposure to BPA 1/5th of 96 h LC50 (1.31 mg/L), brain exhibited oxidative damage, which was evidenced by compromised antioxidant system (CAT, SOD, GSH) and increased level of biomacromolecule peroxidation (MDA and 8-OHDG). Functional damage to the brain observed in the form of blood-brain barrier disruption (decreased tight junction gene expression) and nerve conduction impairment (reduced acetylcholinesterase activity). Mechanistically, apoptotic cell death indicated by characteristic alteration in key biomarkers (bcl-2, caspase, and p53-related gene family). Whereas, coadministration of powdered PP (pomegranate peel) (8 %) with BPA effectively mitigated the BPA toxicity, as evidenced by the restoration of the above-mentioned bioindicators. Thereby, BPA-induced neurotoxicity could be potentially detoxified by applying PP dietary enrichment.

Estrogen Regulated Genes Compel Apoptosis in Breast Cancer Cells, Whilst Stimulate Antitumor Activity in Peritumoral Immune Cells in a Janus-Faced Manner.

Background: Breast cancer incidence and mortality exhibit a rising trend globally among both premenopausal and postmenopausal women, suggesting that there are serious errors in our preventive and therapeutic measures. Purpose: Providing a series of valuable, but misunderstood inventions highlighting the role of increasing estrogen signaling in prevention and therapy of breast cancer instead of its inhibition. Results: 1. Breast cells and breast cancer cells with germline BRCA1/2 mutations similarly show defects in liganded estrogen receptor (ER) signaling, demonstrating its role in genomic instability and cancer initiation. 2. In breast tumors, the increased expression of special receptor family maybe an effort for self-directed improvement of genomic defects, while the weakness or loss of receptors indicates a defect requiring medical repair. 3. ER overexpression in breast cancer cells is capable of strengthening estrogen signaling and DNA repair, while in ER negative tumors, HER2 overexpression tries to upregulate unliganded ER activation and genome stabilization. 4. ER-positive breast cancers responsive to endocrine therapy may show a compensatory ER overexpression resulting in a transient tumor response. Breast cancers non-responsive to antiestrogen treatment exhibit HER2-overexpression for compensating the complete inhibition of hormonal ER activation. 5. In breast tumors, somatic mutations serve upregulation of ER activation via liganded or unliganded pathway helping genome stabilization and apoptotic death. 6. The mutual communication between breast cancer and its inflammatory environment is a wonderful partnership among cells fighting for genome stabilization and apoptotic death of tumor. 7. In breast cancers, there is no resistance to genotoxic or immune blocker therapies, but rather, the nonresponsive tumor cells exhaust all compensatory possibilities against therapeutic damages. Conclusions: Understanding the behavior and ambition of breast cancer cells may achieve a turn in therapy via applying supportive care instead of genotoxic measures.

New insights about the toxicity of 2,4-D: Gene expression analysis reveals modulation on several subcellular responses in Chironomus riparius.

Herbicides are the main class of pesticides applied in crops and are capable of polluting the surrounding freshwater system; thus, understanding their impact on non-target species, whose mechanism of action is not described, helps to elucidate the real risks of these pollutants to the environment. 2,4-dichlorophenoxyacetic acid (2,4-D) is frequently detected in water and, due to its persistence, poses a risk to wildlife. In this way, the present work aimed to describe the implication of exposure to concentrations of 2,4-D already reported in aquatic environments in several physiological mechanisms of C. riparius at molecular and biochemical levels. To achieve this, bioassays were conducted with fourth instar larvae exposed to three concentrations of 2,4-D (0.1, 1.0, and 7.5 µg L-1). Larvae were collected after 24 and 96 h of exposure, and the expression of 42 genes, related to six subcellular mechanisms, was assessed by Real-Time PCR (RT-PCR). Besides, the activity of the enzymes catalase (CAT), glutathione S-transferase (GST), and acetylcholinesterase (AChE) was determined. The main metabolic route altered after exposure to 2,4-D was the endocrine system (mainly related to 20-hydroxyecdysone and juvenile hormone), confirming its endocrine disruptor potential. Four of the eleven stress response genes studied were down-regulated, and later exposure modulated DNA-repair genes suggesting genotoxic capacity. Moreover, only one gene from each detoxification phase was modulated at short exposure to 1.0 µg L-1. The molecular responses were not dose-dependent, and some early responses were not preserved after 96 h, indicating a transient response to the herbicide. Exposure to 2,4-D did not alter the activity of CAT, GST, and AChE enzymes. The responses described in this study reveal new mechanistic pathways of toxicity for 2,4-D in non-target organisms and highlight potential ecological consequences for chironomids in aquatic systems at the edges of agricultural fields.

BPA induces testicular damage in male rodents via apoptosis, autophagy, and ferroptosis.

Bisphenol A (BPA), chemically known as 2,2-bis(4-hydroxyphenyl) propane, is one of the most common endocrine-disrupting chemicals in our environment. Long-term or high-dose exposure to BPA may lead to testicular damage and adversely affect male reproductive function. In vivo studies on rodents have demonstrated that BPA triggers apoptosis in testicular cells through both intrinsic and extrinsic pathways. Further in vitro studies on spermatogonia, Sertoli cells, and Leydig cells have all confirmed the pro-apoptotic effects of BPA. Given these findings, apoptosis is considered a primary mode of cell death induced by BPA in testicular tissue. In addition, BPA promotes autophagy by altering the activity of the Akt/mTOR pathway and upregulating the expression of autophagy-related genes and proteins. Recent studies have also identified ferroptosis as a significant contributing factor to BPA-induced testicular damage, further complicating the landscape of BPA's effects. This review summarizes natural substances that mitigate BPA-induced testicular damage by inhibiting these cell death pathways. These findings not only highlight potential therapeutic strategies but also underscore the need for further research into the underlying mechanisms of BPA-induced toxicity, particularly as it pertains to human health risk assessment and the development of more effective BPA management strategies.

The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women.

Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are androgen excess disorders requiring the determination of classic androgen levels for diagnosis. 11-oxygenated androgens have high androgenic potential, yet their clinical value in those disorders is not clear. Additionally, the role of endocrine disruptors (EDs), particularly in IH, remains understudied. We analyzed 25 steroids and 18 EDs in plasma samples from women with IH, PCOS, and controls using LC-MS/MS. Cytokine levels and metabolic parameters were assessed. Comparisons included non-obese women with PCOS (n = 10), women with IH (n = 12) and controls (n = 20), and non-obese versus obese women with PCOS (n = 9). Higher levels of 11-oxygenated androgens were observed in women with PCOS compared to those with IH, but not controls. Conversely, 11-oxygenated androgen levels were lower in women with IH compared to controls. Cytokine levels did not differ between women with IH and controls. Bisphenol A (BPA) levels were higher in obese women with PCOS compared to non-obese women with PCOS. Bisphenol S occurrence was higher in women with PCOS (90%) compared to controls (65%) and IH (50%). Significant correlations were found between androgens (11-ketotestosterone, androstenedione, testosterone) and insulin and HOMA-IR, as well as between immunomodulatory 7-oxygenated metabolites of DHEA and nine interleukins. Our data confirms that PCOS is a multiendocrine gland disorder. Higher BPA levels in obese women might exacerbate metabolic abnormalities. IH was not confirmed as an inflammatory state, and no differences in BPA levels suggest BPA does not play a role in IH pathogenesis.

The Impact of Polychlorinated Biphenyls on the Development of Zebrafish (Danio rerio).

Polychlorinated biphenyls (PCBs) are a group of 209 highly stable molecules that were used extensively in industry. Although their commercial use ceased in 1979, they are still present in many aquatic ecosystems due to improper disposal, oceanic currents, atmospheric deposition, and hydrophobic nature. PCBs pose a significant and ongoing threat to the development and sustainability of aquatic organisms. In areas with PCB exposure high mortality rates of organisms inhabiting them are still seen today, posing a significant threat to local species. Zebrafish were exposed to a standard PCB mixture (Aroclor 1254) for the first 5 days post fertilization, as there is a gap in knowledge during this important developmental period for fish (i.e., organization of the body). This PCB mixture was formally available commercially and has a high prevalence in PCB-contaminated sites. We tested for the effects of PCB dosage (control (embryo water only; 0 mg/L), methanol (solvent control; 0 mg/L); PCB 1 (0.125 mg/L), PCB 2 (0.25 mg/L), PCB 3 (0.35 mg/L), and PCB 4 (0.40 mg/L)) on zebrafish survival, rate of metamorphosis, feeding efficiency, and growth. We found significant, dose-dependent effects of PCB exposure on mortality, feeding efficiency, and growth, but no clear effect of PCBs on the rate of zebrafish metamorphosis. We identified a concentration in which there were no observable effects (NOEC), PCB concentration above the NOEC had a significant impact on life-critical processes. This can further inform local management decisions in environments experiencing PCB contamination.

Effects of hypoxia on the reproductive endocrine axis of the pejerrey (Odontesthes bonariensis).

Recently, hypoxic areas have been identified in water bodies of the Pampas region due to human activity. The objective of this work was to study the effect of low concentrations of dissolved oxygen (hypoxia) on the reproductive endocrine axis of a pampas fish (Odontesthes bonariensis). Groups of 8 males and 8 females were subjected to severe hypoxia (2-3 mg l-1) and normoxia (7-9 mg l-1) in 3000 l tanks by duplicate during the reproductive season (spring). After 21 days, 4 males and 4 females from each tank were sacrificed, and blood was drawn to measure estradiol (E2) and testosterone (T). The brain, pituitary gland and a portion of the gonads were extracted and processed to measure the expression of: gnrh1, cyp19a1b, fshß, lhß, fshr, lhcgr and cyp19a1a. From the second experimental week, no spawning was found in the hypoxic females, while at the end of the treatment period no male released sperm. Fish under hypoxic conditions showed signs of gonadal regression, reduction of GSI and plasma levels of sex steroids. Furthermore, the expression of gnrh1 in both sexes, cyp19a1b and fshr in males and only fshß and cyp19a1a in females decreased in comparison with normoxic fish. After 40 days under normal conditions, signs of reproductive recovery were observed in the treated fish. The results obtained demonstrated that hypoxia generated an inhibition of some components of the pejerrey's reproductive endocrine axis, but the effect was reversible.

Bacterial bioremediation as a sustainable strategy for the mitigation of Bisphenol-A.

In the era dominated by plastic, the widespread use of plastic in our daily lives has led to a growing accumulation of its degraded byproducts, such as microplastics and plastic additives like Bisphenol A (BPA). BPA is recognized as one of the earliest man-made substances that exhibit endocrine-disrupting properties. It is frequently employed in the manufacturing of epoxy resins, polycarbonates, dental fillings, food storage containers, infant bottles, and water containers. BPA is linked to a range of health issues including obesity, diabetes, chronic respiratory illnesses, cardiovascular diseases, and reproductive abnormalities. This study examines the bacterial bioremediation of the BPA, which is found in many sources and is known for its hazardous effects on the environment. The metabolic pathways for the breakdown of BPA in important bacterial strains were hypothesized based on the observed altered intermediate metabolites during the degradation of BPA. This review discusses the enzymes and genes involved in the bacterial degradation of BPA. The utilization of naturally occurring microorganisms is the most efficient and cost-effective method due to their selectivity of strains, ensuring sustainability.

Environmental endocrine disruptor-induced mitochondrial dysfunction: a potential mechanism underlying diabetes and its complications.

Diabetes and its complications significantly affect individuals' quality of life. The etiology of diabetes mellitus and its associated complications is complex and not yet fully understood. There is an increasing emphasis on investigating the effects of endocrine disruptors on diabetes, as these substances can impact cellular processes, energy production, and utilization, ultimately leading to disturbances in energy homeostasis. Mitochondria play a crucial role in cellular energy generation, and any impairment in these organelles can increase susceptibility to diabetes. This review examines the most recent epidemiological and pathogenic evidence concerning the link between endocrine disruptors and diabetes, including its complications. The analysis suggests that endocrine disruptor-induced mitochondrial dysfunction-characterized by disruptions in the mitochondrial electron transport chain, dysregulation of calcium ions (Ca2+), overproduction of reactive oxygen species (ROS), and initiation of signaling pathways related to mitochondrial apoptosis-may be key mechanisms connecting endocrine disruptors to the development of diabetes and its complications.

Prenatal exposure to dibutyl phthalate contributes to erectile dysfunction in offspring male rats by activating the RhoA/ROCK signalling pathway.

Prenatal exposure to dibutyl phthalate (DBP) has been reported to cause erectile dysfunction (ED) in adult offspring rats. However, its underlying mechanisms are not fully understood. Previously, we found that DBP activates the RhoA/ROCK pathway in the male reproductive system. This study investigated how prenatal exposure to DBP activates the RhoA/ROCK signalling pathway, leading to ED in male rat offspring. Pregnant rats were stratified into DBP-exposed and NC groups, with the exposed group receiving 750 milligrams per kilogram per day (mg/kg/day) of DBP through gavage from days 14-18 of gestation. DBP exposure activated the RhoA/ROCK pathway in the penile corpus cavernosum (CC) of descendants, causing smooth muscle cell contraction, fibrosis, and apoptosis, all of which contribute to ED. In vitro experiments confirmed that DBP induces apoptosis and RhoA/ROCK pathway activation in CC smooth muscle cells. Treatment of DBP-exposed offspring with the ROCK inhibitor Y-27632 for 8 weeks significantly improved smooth muscle cell condition, erectile function, and reduced fibrosis. Thus, prenatal DBP exposure induces ED in offspring through RhoA/ROCK pathway activation, and the ROCK inhibitor Y-27632 shows potential as an effective treatment for DBP-induced ED.

Perinatal exposure to Aroclor 1254 disrupts thyrotropin-releasing hormone mRNA expression in the paraventricular nucleus of male and female rats.

Polychlorinated biphenyls (PCBs) are industrial pollutants that act as endocrine disruptors and alter thyroid function. However, it is still unclear whether PCBs can affect hypothalamic thyrotropin releasing hormone (Trh) mRNA expression through TH signaling disruption. As salt-loading dehydration induces tertiary hypothyroidism in the hypothalamic parvocellular paraventricular nuclei (paPVN), and perinatal exposure to Aroclor 1254 (A1254) disrupts the hydric balance in rats, we hypothesized that TRH synthesis could be altered during dehydration in TRH neurons that control the hypothalamic-pituitary-thyroid (HPT) axis activity in rats perinatally exposed to A1254. We examined Trh mRNA expression in the paPVN and the response to salt-loading dehydration (hyperosmotic (hyper) stress) in the progeny of Wistar pregnant rats receiving 0 mg/kg BW (control) or 30 mg/kg BW A1254 daily from gestational days 10-19. Three-month-old offspring were subjected to normosmotic or hyper conditions and Trh mRNA, glucocorticoid receptor (GR) mRNA expression were measured in the PVN by RT-PCR. TRH mRNA and TRH+ neurons were measured in the paPVN by fluorescent in situ hybridization (FISH). As expected, Trh mRNA levels were decreased in the paPVN of male and female rats in the hyper group. Basal Trh mRNA expression and serum TSH were decreased in male rats in the A1254 group. Notably, Trh mRNA levels were further decreased in the paPVN of male and female A1254 + hyper rats, in which the GR mRNA expression was significantly decreased. These results support the hypothesis that perinatal exposure to A1254 results in inadequate adaptive response of the HPT axis in adulthood and contributes to dysregulation of the HPT axis response to salt-loading dehydration.

Exposure to endocrine disruptor DEHP promotes the progression and radiotherapy resistance of pancreatic cancer cells by increasing BMI1 expression and properties of cancer stem cells.

Most patients diagnosed with pancreatic cancer are initially at an advanced stage, and radiotherapy resistance impact the effectiveness of treatment. This study aims to investigate the effects of endocrine disruptor Di-(2-ethylhexyl) phthalate (DEHP) on various biological behaviors and the radiotherapy sensitivity of pancreatic cancer cells, as well as its potential mechanisms. Our findings indicate that exposure to DEHP promotes the proliferation of various cancer cells, including those from the lung, breast, pancreas, and liver, in a time- and concentration-dependent manner. Furthermore, DEHP exposure could influence several biological behaviors of pancreatic cancer cells in vivo and vitro. These effects include reducing cell apoptosis, causing G0/G1 phase arrest, increasing migration capacity, enhancing tumorigenicity, elevating the proportion of cancer stem cells (CSCs), and upregulating expression levels of CSCs markers such as CD133 and BMI1. DEHP exposure can also increase radiation resistance, which can be reversed by downregulating BMI1 expression. In summary our research suggests that DEHP exposure can lead to pancreatic cancer progression and radiotherapy resistance, and the mechanism may be related to the upregulation of BMI1 expression, which leads to the increase of CSCs properties.

Titanium dioxide nanoparticles Disrupt ultrastructure and function of Rat thyroid tissue via oxidative stress.

Nano-TiO2 is widely used in various fields such as industry, daily necessities, food and medicine. Previous studies have shown that it can enter mammalian tissues through the digestive tract or respiratory tract and have effects on various organs and systems. However, the effect of nano-TiO2 on the mammalian thyroid gland has not been reported. In this study, we fed SD rats with rutile nano-TiO2 at a dose of 5 mg/kg body weight for 3 weeks, and then examined the thyroid histology and thyroid function of the rats. In vitro experiments were conducted to determine the effects of nano-TiO2 on the viability, apoptosis, inflammatory factors, antioxidant enzymes, and oxidative stress of human thyroid follicular epithelial cells. Histological evidence showed abnormal morphology of rat thyroid follicles and organelle damage in follicular epithelial cells. Nano-TiO2 caused a decrease in the level of sodium/iodide symporter (NIS), an increase in the level of apoptotic protein cleaved-caspase 3, and an increase in the levels of pro-inflammatory factors IL-1ß and TNF-α in rat thyroid tissue. Nano-TiO2 also resulted in increased serum FT4 and TPO-Ab levels. In in vitro experiments, nano-TiO2 reduced the viability of human thyroid follicular cells, downregulated the levels and activities of antioxidant enzymes CAT, GPX1 and SOD, and increased the levels of ROS and MDA caused by oxidative stress. These results indicate that nano-TiO2 damages the structure and function of thyroid follicular epithelial cells through oxidative stress. Long-term exposure to nano-TiO2 could be a potential risk factor for thyroid dysfunction.

Bisphenol AF Caused Reproductive Toxicity in Rats and Cineole Co-Treatment Exhibited Protective Effect.

Bisphenol AF (BPAF) is increasingly used and now found in products intended for human consumption. The protective effect of 1,8-cineole (CIN) against BPAF-induced reproductive toxicity was investigated. Four groups were created, with each group consisting of eight rats: control, BPAF (200 mg/kg), CIN (200 mg/kg), and BPAF + CIN groups. The results demonstrated that the BPAF group exhibited a decline in testosterone levels and a decrease in sperm parameters compared with the control. Additionally, higher levels of MDA were observed, along with lower levels of GSH and GPx activity. CAT activity also decreased slightly. Tnf-α, Nf-κB levels were significantly higher, and caspase-3 expression was elevated, while PCNA expression decreased. BPAF significantly increased tissue degeneration compared with the control. However, the BPAF + CIN group showed statistically significant improvements in sperm parameters, except for concentration. They also exhibited an increase in testosterone levels and an improvement in MDA and GSH levels compared with the BPAF group. However, GPx activity partially enhanced. Tnf-α and Nf-κB levels were significantly reduced, and caspase-3 levels declined while PCNA and Bcl-2 levels increased. The Johnsen Testicular Biopsy score showed a substantial increase. Overall, these results suggest that CIN co-treatment in rats enhanced reproductive health and exhibited antioxidant, antiapoptotic, and anti-inflammatory properties against BPAF-induced testicular damage.

Evaluation of Bisphenol S (BPS) toxicity on the reproductive system of Channa striatus: Insights for environmental risk assessment.

Aquatic ecosystems face significant exposure to endocrine-disrupting chemicals (EDCs), which can mimic, block, or alter the synthesis of endogenous hormones. Bisphenol A (BPA), a widely known EDC, has been phased out from consumer products due to concerns about its potential impacts on human health. In its place, bisphenol S (BPS), an organic compound, has been increasingly used in the production of polycarbonate plastics, epoxy resins, thermal receipt papers, and currency. Vitellogenin (Vtg), a yolk precursor protein synthesized in the liver and present in oviparous fish, particularly males, serves as a pertinent biomarker for studying the effects of estrogenic EDCs on fish. This study aimed to assess the impact of BPS on reproductive parameters and hepatic vitellogenin expression in Channa striatus. The LC50 of BPS was determined to be 128.8 mg/L. Experimental groups included control and BPS-exposed fish, with sub-lethal concentrations of BPS (1 mg/L, 4 mg/L, and 12 mg/L) administered and effects monitored at seven- and twenty-one-day intervals. Significant decreases in gonadosomatic index (GSI), ova diameter, and fecundity were observed in BPS-exposed Channa striatus. Hepatic Vtg mRNA expression was downregulated in female and upregulated in male following BPS exposure. Serum hormone analysis confirmed the estrogenic activity of BPS. These findings underscore BPS's ability as an endocrine disruptor to interfere with hormone synthesis and disrupt spermatogenesis and oogenesis processes in Channa striatus. This research contributes to understanding the endocrine-disrupting effects of BPS on aquatic organisms, highlighting potential ecological implications and the need for continued monitoring and regulatory considerations.

Vitamin E alleviates glyphosate-based herbicide-induced progesterone secretion inhibition and oxidative stress increase in chicken primary granulosa cells.

Glyphosate-based herbicides (GBH) are the most extensively used herbicides worldwide. Despite a presumed nondangerousness for animals, several studies reported negative effects after a GBH exposure in several animal models including birds, notably on reproductive functions. Several studies concerning the advantages of Vitamin E (VE) for antioxidant activity but also growth and reproduction have been reported in birds. However, it remains unclear whether VE could alleviate the negative effect of GBHs on chicken ovarian cells. Here we exposed chicken primary granulosa cells (GCs) from F1 and F3/4 follicles to growing doses of GBH (0.036, 0.36, 3.6, and 36 gly eq/L), with or without VE supplementation (1 mg/L) and investigated cell viability, proliferation, oxidative stress and steroidogenesis. GBH exposure did not affect F1 and F3 GCs viability but it increased cell proliferation only in F1 GCs and this effect was not altered by VE. In both F1 and F3/4 GCs, GBH exposure increased total oxidant status (TOS), reduced total antioxidant status (TAS) and consequently increased index of oxidative stress (OSI) in dose dependent manner. This latter effect for GBH 36 mg eq gly/L was totally abolished in response to VE. In both F1 and F3/4 GCs, GBH exposure reduced progesterone secretion in a dose dependent manner and this effect with GBH 0.36 and 1.8 mg eq glyphosate/L was alleviated by VE. However, we did not observe any effect of GBH and VE on the gene expression of several components of the steroidogenesis process. Taken together, these results show that GBH may have endocrine disruptor effects, and that these effects might be alleviated by antioxidant VE supplementation.

Effects of Bisphenol A on Male Gonadal Tissue of Viviparous Fish: Histopathological Evidence in Goodea atripinnis / Efectos del Bisfenol A en tejido Gonadal Masculino de Peces Vivíparos: Evidencia Histopatológica en Goodea atripinnis

SUMMARY: BPA is a multifunctional endocrine disruptor with ubiquitous presence in aquatic ecosystems. The Mexican Central Plateau is an area severely impacted by pollution, inhabited by endemic viviparous fish. However, efforts to understand the effects of BPA on native species such as Goodea atripinnis are non-existent. This study focused on providing in vivo evidence of alterations in the testes of G. atripinnis males due to acute exposure to BPA at test concentrations of 1 mg/L, 10 mg/L, and 50 mg/L for 96 h. BPA exposition 1 mg/L and 10 mg/L showed degeneration and disorganization in germinal tissue. Furthermore, there was a notable decrease in sperm within the seminiferous tubules of males exposed to 10 mg/L of BPA. In all treatments, somatic cells had alterations by connective tissue thickening and an increase in collagen fibers. Additionally, inflammation and bleeding occurred in the testes of males exposed to 1 and 10 mg/L BPA. The alterations in the testes of G. atripinnis are related to BPA toxicity, which can lead to apoptosis in germ cells increasing connective tissue. Finally, even though the changes produced by BPA became evident in acute exposure (96 h), its effects are probably irreversible, compromising the reproduction of G. atripinnis.

El BPA es un disruptor endocrino multifuncional con presencia ubicua en los ecosistemas acuáticos. La Meseta Central mexicana habitada por peces vivíparos endémicos, es una zona severamente impactada por la contaminación. Sin embargo, los esfuerzos por comprender los efectos del BPA en especies nativas como Goodea atripinnis son inexistentes. Este estudio se centró en proporcionar evidencia in vivo de alteraciones en los testículos de machos de G. atripinnis debido a la exposición aguda al BPA en concentraciones de prueba de 1 mg/L, 10 mg/L y 50 mg/L durante 96 h. La exposición a BPA 1 mg/L y 10 mg/L mostró degeneración y desorganización en el tejido germinal. Además, hubo una disminución notable de los espermatozoides dentro de los túbulos seminíferos de machos expuestos a 10 mg/L de BPA. En todos los tratamientos las células somáticas presentaron alteraciones por engrosamiento del tejido conectivo y aumento de las fibras de colágeno. Además, se produjo inflamación y sangrado en los testículos de machos expuestos a 1 y 10 mg/L de BPA. Las alteraciones en los testículos de G. atripinnis están relacionadas con la toxicidad del BPA, lo que puede provocar apoptosis en las células germinales aumentando el tejido conectivo. Finalmente, si bien los cambios producidos por el BPA se hicieron evidentes en la exposición aguda (96 h), sus efectos probablemente sean irreversibles, comprometiendo la reproducción de G. atripinnis.

Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance.

The Adverse Outcome Pathway (AOP) framework has gained widespread acceptance in toxicological disciplines as a tool for aiding chemical hazard assessment. Despite increased activity in AOP development, progress towards a high volume of fully endorsed AOPs has been slow, partly due to the challenging task of constructing complete AOPs according to the AOP Developer's Handbook. To facilitate greater uptake of new knowledge units onto the open-source AOP-wiki platform, a pragmatic approach was recently proposed. This approach involves considering Key Event Relationships (KERs) for individual development through systematic approaches, as they represent essential units of knowledge from which causality can be inferred; from low complexity test data to adverse outcomes in intact organisms. However, more broadly adopted harmonized methodologies for KER development would be desirable. Using the AOP Developer's Handbook as a guide, a KER linking 'decreased androgen receptor (AR) activity' with 'reduced anogenital distance (AGD)' was developed to demonstrate a methodology applicable for future developments of KERs requiring systematic literature retrieval approaches.

Acute effects of atrazine on the immunoexpressions of sertoli and germ cells molecular markers, cytokines, chemokines, and sex hormones levels in mice testes and epididymides.

Atrazine is currently one of the most commonly used agrochemicals in the United States and elsewhere. Here, we studied the immunoexpression of molecular markers of mammalian testicular functions: androgen receptor (AR), promyelocytic leukemia zinc finger (PLZF), GDNF family receptor alpha-1 (GFRA1), VASA/DDX4 (DEAD-Box Helicase 4) as well as the levels of intratesticular and intra-epididymal estradiol (E2) and dihydrotestosterone (DHT), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins (IL-1ß and IL-6, IL-10) and testicular chemokines (CXCL-1, CCL-2 and CCL3) in BalB/c mice after a sub-acute gavage treatment with a gonado-toxin, atrazine (50 mg/kg body wt.) for three days. We found high numbers of AR immunopositive Sertoli cells and low numbers of GFRA1, PLZF and VASA/DDX4-positive germ cells in the seminiferous tubule regions of the testes. While TNF-α level in the testes fell and remained unchanged in the epididymides, IFN-γ levels in the testes remained constant but increased in the epididymides. E2 and DHT concentrations remained unaltered in the testes but were changed in the epididymides. There were no significant changes in the levels of interleukins in the testis and epididymis. Intratesticular chemokines were also not significantly altered, except for CCL-4, which was increased in the testis. Light microscopy of the epididymis showed detached epithelium and some detached cells in the lumen. It is concluded that atrazine changed the inflammatory status of the gonads and highlighted Sertoli and undifferentiated spermatogonia as important targets for atrazine's toxic effects in the testis of mice. Concerning the epididymis, atrazine altered the epididymal hormonal concentrations and promoted histopathological modifications in its parenchyma.

Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study.

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.