Toxicological Sciences最新文献

{"title":"Nicotinamide mononucleotide ameliorates impaired testicular spermatogenesis in uranium-exposed mice by modulating glycolytic pathways.","authors":"Hui Wu, Bingsheng Huang, Ziyu Zhou, Xiaocan Lei, Yu Zhang, Wendian She, Qingwen Peng, Yueze Zhu, Junli Wang, Mingyou Dong","doi":"10.1093/toxsci/kfaf068","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf068","url":null,"abstract":"<p><p>Natural uranium is a ubiquitous element in the environment, and human exposure to low levels of uranium is unavoidable. Several concerns have recently been raised about the reproductive effects of chronic exposure to low levels of uranium. Therefore, the aim of this study was to investigate the protective effect of Nicotinamide mononucleotide（NMN） on uranium exposure-induced testicular sperm function in mice. To this end, a research model was established in which testicular damage and spermatogenic dysfunction were induced in adult male mice by intraperitoneal injection of two different doses of uranyl nitrate. Following a week of intraperitoneal injection, the mice were given oral doses of 500 mg/kg of NMN, a dose that was validated in an in vitro cellular model. The results demonstrated a decline in testicular weight and epididymis weight, along with a reduction in sperm count, in comparison to the control group. Subsequent observation of testicular morphology revealed the presence of disorganized seminiferous tubules, characterized by reduced area and diameter. Concurrently, a downregulation of the anti-apoptotic factor (Bcl-2) and an upregulation of the apoptotic factor (Bax) were observed in the testis. Furthermore, an analysis of testicular genetic expression levels of Sertoli cell (SCs) markers (WT-1, Sox9, PCNA, and Vimentin) revealed a substantial exacerbation of pathological changes, including an augmentation in the severity of tubular degeneration. NMN treatment resulted in a significant enhancement of testicular function, as evidenced by an increase in epididymal and testicular weights, as well as sperm counts, when compared to saline-treated uranium-exposed mice.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perfluorooctane sulfonate (PFOS) exposure and alcohol-associated liver disease severity in a mouse chronic-binge ethanol feeding model.","authors":"Frederick A Ekuban, Tyler C Gripshover, Paxton Ames, Kushal Biswas, Oluwanifemi E Bolatimi, Joshua Abramson, Megana Iyer, Jianzhu Luo, Abigail Ekuban, Jae Yeon Hwang, Juw Won Park, Mayukh Banerjee, Walter H Watson, Banrida Wahlang, Dhimiter Bello, Jennifer J Schlezinger, Craig J McClain, Matthew C Cave","doi":"10.1093/toxsci/kfaf066","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf066","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Exposure to pollutants including the ubiquitous 'forever chemical', Perfluorooctane sulfonate (PFOS) has increasingly been associated with metabolic dysfunction-associated steatotic liver disease (MASLD). Recent epidemiological evidence has identified associations between Per- and polyfluoroalkyl substances (PFAS) exposure and increased liver injury in alcohol consumers, suggesting potential interactions between these exposures. However, the intersection of pollutant exposures and alcohol-associated liver disease (ALD) is not well studied. We hypothesize that pollutants may disrupt hepatic metabolism to modify ALD severity. Recently, we developed a two-hit (ethanol plus pollutant) mouse model, enabling testing of this hypothesis. Here, we elucidate the metabolic and disease-modifying effects of PFOS in this model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Male C57BL/6J mice were fed isocaloric control or 5% Ethanol (EtOH) Lieber-DeCarli diet for 15 days. From day 6 of feeding, mice were concurrently gavaged with 1 mg/kg PFOS or 2% tween-80 vehicle for 10 days, followed by a 5 g/kg EtOH binge dose and euthanized 5-6 hours later.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Approximately 60% of the administered PFOS dose accumulated in liver. PFOS exacerbated EtOH-induced hepatic steatosis and was associated by higher levels of plasma very low-density lipoprotein (vLDL) and alanine aminotransferase (ALT). PFOS upregulated hepatic ethanol-metabolizing enzymes and lowered blood alcohol levels. Ingenuity Pathway Analysis (IPA) Top Toxicity Functions/Lists associated with hepatic gene expression following PFOS co-exposure in EtOH-fed mice included: Fatty acid metabolism and liver steatosis; nuclear receptor activation, cytochrome P450, and reactive oxygen species (ROS); apoptosis; liver fibrosis; and hepatocellular carcinoma (HCC). GO/KEGG analyses similarly revealed enrichment in fatty acid, xenobiotic, alcohol, or glutathione metabolic processes; and Peroxisome proliferator-activated receptor (PPAR) signaling. PFOS upregulated hepatic expression of several nuclear receptors (e.g., Pparα, Car, and Pxr) and their P450 target genes (e.g., Cyp4a10, Cyp2b10, and Cyp3a11) by RT-PCR or Western blot, confirming key IPA predictions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PFOS is a metabolism disrupting chemical that worsened ALD severity. PFOS activated hepatic nuclear receptors and enriched hepatic transcriptional pathways associated with steatosis, xenobiotic metabolism, oxidative stress, cell death, fibrosis, and HCC. These data demonstrate a novel mechanism whereby PFOS exacerbates ALD through coordinated dysregulation of lipid homeostasis and liver injury, potentially mediated by nuclear receptor activation. The identification of PFOS as an ALD risk modifier highlight the critical need to evaluate environmental pollutants as potential contributors to liver disease progression. More data are required on environmental pollution as a disease modifying","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying Environmental Chemicals Impacting Neurodevelopment using a random Mixture-Based Screening Approach.","authors":"Wenxin Hu, Lei Xing, Jieun Park, Bonnie Taylor-Blake, James L Krantz, Yun-Chung Hsiao, Chih-Wei Liu, Sophia U Lamberti, Kun Lu, Mark J Zylka","doi":"10.1093/toxsci/kfaf067","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf067","url":null,"abstract":"<p><p>Environmental exposures can impact brain development and contribute to neurodevelopmental disorder risk. In this study, we leveraged insights from in vitro high-throughput screening studies that examined the developmental toxicity of environmental chemicals to select 47 chemicals for in vivo testing as complex random mixtures in pregnant female mice. Our objectives were to identify mixtures that impact key neurodevelopmental endpoints-embryonic body, brain, and placenta weight-and subsequently to use mass spectrometry to ascertain which chemicals from each active mixture entered the developing brain following gestational exposure. We identified three chemicals that entered the embryonic brain and reduced embryonic brain weight: perfluorooctanoic acid (PFOA), fenpyroximate, and 4-tert-octylphenol. Given its effect on embryonic brain weight and its widespread presence in environmental samples, we selected PFOA for further study using single-nuclei RNA sequencing. We found that PFOA altered neural progenitor cell proliferation and neuronal differentiation in the developing mouse cerebral cortex. Furthermore, we found that gestational exposure to PFOA disrupted neurodevelopment by altering the cell cycle in neural progenitor cells of males and females. In conclusion, we identified environmental chemicals that impact neurodevelopmental processes in vivo and found that single nuclei RNA sequencing can provide new insights into the cellular mechanism of neurotoxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An FDA/CDER nonclinical perspective on the use of hiPSC-CM data for cardiovascular safety assessment and regulatory decisions.","authors":"Natalie E Simpson, Todd Bourcier, Nakissa Sadrieh","doi":"10.1093/toxsci/kfaf064","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf064","url":null,"abstract":"<p><p>Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a New Approach Methodology (NAM) used in regulatory submissions to the U.S Food and Drug Administration (FDA). This article builds on the previous FDA analysis using a new search strategy to provide an updated landscape of hiPSC-CM studies submitted to the FDA for review. The current search method is more comprehensive than the previous ones, emphasizing the importance of standardized keywords in study titles for easier identification of NAMs submitted to FDA. Here the authors report an increase in hiPSC-CM studies submitted to FDA, with most using the multielectrode array (MEA) platform. In this new analysis, the authors observed that the study methodology, context of use (COU), and reasons for submission are often unclear, despite their importance for regulatory acceptance and review. hiPSC-CM study results are not discussed in many archived reviews, suggesting limited impact on regulatory decisions. Detailed reporting to characterize the clinical relevance of findings and systematic submission of hiPSC-CM studies to better understand their predictivity compared to familiar nonclinical assessment methods are key components from a Pharmacology/Toxicology perspective to increase regulatory use of this subset of NAMs.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental exposure to 1,4-dioxane, a volatile organic compound of emerging concern, induces immediate phenotypic, transcriptomic, and adult-onset neurodevelopmental effects.","authors":"Mackenzie L Connell, Camille Akemann, Chia-Chen Wu, Emily Kintzele, Emma Cavaneau, Gabrielle F Gonzalez, Bridget B Baker, Tracie R Baker","doi":"10.1093/toxsci/kfaf063","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf063","url":null,"abstract":"<p><p>1,4-dioxane, a synthetic volatile organic compound (VOC), has been found in products including paints, cosmetics, and pesticides as well as food products and drinking water. Contamination in groundwater poses significant environmental and public health risks due to its high mobility and widespread human exposure through vapor intrusion and multi-route exposure pathways. Adverse health effects have been observed as a result of exposure to this compound; however, there is little research on the developmental and reproductive effects. Controlled VOC exposures (0.004, 0.40, and 40 parts per million (ppm)) of zebrafish embryos were conducted in sealed glass vials over a developmental period (120 hours). Endpoints evaluated were mortality, abnormalities, larval behavior, transcriptomics, and adult-onset effects. The behavior of zebrafish larvae was significantly altered for the 40 ppm group. Expression of key genes (insig1, tbc1d10aa) were observed immediately following exposure and some persisted into adulthood. The top dysregulated diseases and disorders pathways in every concentration were cancer, organismal injury and abnormality, endocrine system disorders, gastrointestinal disease, and neurological disorders. Pathways of note enriched in larval and adult tissues include endocrine gland tumorigenesis, insulin resistance, movement disorders, cell survival, and cellular homeostasis. Specific reproductive pathways included pelvic, genital, uterine, and mammary tumors and carcinomas, however, there was no significant effect on adult zebrafish fertility. This study moves the field forward by integrating a novel zebrafish model and lifespan approach shedding new light on understudied implications of low-level VOC exposure, ultimately informing public health policies to mitigate the risks associated with this ubiquitous environmental contaminant.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies.","authors":"Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu","doi":"10.1093/toxsci/kfaf060","DOIUrl":"10.1093/toxsci/kfaf060","url":null,"abstract":"<p><p>The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the three isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies.","authors":"Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu","doi":"10.1093/toxsci/kfaf059","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf059","url":null,"abstract":"<p><p>The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the three isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporating Metabolic Competence into High-Throughput Profiling Assays.","authors":"Amanda Jurgelewicz, Kristen Breaux, Clinton M Willis, Felix R Harris, Gabrielle Byrd, Joshua Witten, Derik E Haggard, Joseph L Bundy, Logan J Everett, Chad Deisenroth, Joshua A Harrill","doi":"10.1093/toxsci/kfaf061","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf061","url":null,"abstract":"<p><p>High-throughput profiling assays such as high-throughput phenotypic profiling (HTPP) with Cell Painting and high-throughput transcriptomics (HTTr) with TempO-SeqTM have been used to characterize the bioactivity and potential hazards associated with large inventories of chemicals. Although both methods offer broad coverage of molecular targets, a limitation is that the cell types used in these in vitro assays typically lack the xenobiotic metabolism capabilities of humans or laboratory animals used for in vivo testing. To address this limitation, this proof-of-concept study coupled the Alginate Immobilization of Metabolic Enzymes (AIME) platform to both assays and evaluated the impact of metabolism on chemical bioactivity in a breast cancer cell line, VM7Luc4E2. HTPP detected concentration-dependent increases in chemical bioactivity corresponding to increased estrogen receptor (ER) activation measured using an ER transactivation assay (ERTA) that had been previously coupled to the AIME platform in VM7Luc4E2 cells. Additionally, HTTr detected a greater number of active genes in the metabolic condition associated with increased ER activation. This corresponded to a greater number of active ER high-confidence (ERHC) gene signatures and/or metabolism-induced shifts in ERHC signature enrichment as a transcriptomic readout of ER activity. This study demonstrates that the high-throughput profiling assays can detect changes in chemical bioactivity between parent compounds and metabolites generated using the AIME platform in a reproducible way. Incorporating metabolic competence into high-throughput profiling assays will better inform next generation risk assessment by capturing potential metabolite-based changes in bioactivity of test chemicals that may be missed by current screening approaches.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distribution of perfluorooctanoic acid in exposed female postpubertal pigs in thermal neutral or heat-stressed conditions.","authors":"Samantha L Good, Collins Antwi-Boasiako, M Estefanía González-Alvarez, Bridget M Buol, Lance H Baumgard, Aileen F Keating, Joseph A Charbonnet","doi":"10.1093/toxsci/kfaf013","DOIUrl":"10.1093/toxsci/kfaf013","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA), a legacy perfluoroalkyl substance with immuno- and repro-toxicant effects, has poorly characterized bioaccumulation and distribution patterns in postpubertal female pigs. The potential for heat stress (HS) to influence PFOA partitioning, potentially through intestinal hyperpermeability and alterations in systemic blood flow, also warrants investigation. This study investigated PFOA uptake, accumulation, and distribution in thermal neutral (TN) and heat-stressed gilts. Pigs (n = 48) were estrus synchronized and experienced TN (20 °C) or HS (26.6 to 32.2 °C) conditions during which they consumed 70 ng/kg bodyweight PFOA via cookie dough as vehicle control daily. Plasma was collected on d 1, 15, and 20. Liver, ovary, and follicular fluid were collected at euthanasia (d 20). Post-exposure, PFOA was detected in serum, liver, ovary, and follicular fluid. HS increased (P < 0.05) plasma PFOA compared with TN pigs on d 15, but on d 20, plasma PFOA levels in TN and HS pigs were similar. Liver PFOA concentrations were similar between TN and HS pigs. Ovarian PFOA levels tended (P = 0.06) to be higher in TN relative to HS pigs, with an opposing pattern in follicular fluid, in which PFOA concentrations were greater (P < 0.05) in HS pigs. These findings suggest that PFOA apportions to plasma, liver, ovary, and follicular fluid of exposed pigs and that HS alters PFOA distribution, which could negatively impact reproductive health. This study underscores the need to consider the interaction of HS and toxicant exposure in environmental health risk assessments.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"143-153"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of dopamine agonists on the estradiol-induced prolactin surge in ovariectomized female Wistar Han rats.","authors":"Atish Patel, Travis L Calkins, Justin D Vidal, Pragati S Coder, Scott Carrier, Giri Gokulrangan, Ananth Srinivas R Chakilam, Sandeep Akare, Richard J Briscoe, Madhu S Mondal","doi":"10.1093/toxsci/kfaf027","DOIUrl":"10.1093/toxsci/kfaf027","url":null,"abstract":"<p><p>Dopamine agonists (DAs) are approved for the treatment of hypodopaminergic pathologies, including Parkinson's disease, restless legs syndrome, and periodic limb movement disorder. During drug development, drugs acting on dopaminergic receptors are often associated with a rat-specific endocrine tumor response, including changes in fertility, which are ascribed to DA-induced suppression of pituitary prolactin release. Although these effects are not observed in or relevant to humans, given species differences in the effects of prolactin on reproductive organs, modeling DA-mediated changes in prolactin and the reproductive system remains important for preclinical drug development. We investigated the effects of 2 D2/D3 DAs, pergolide and rotigotine, on the estradiol (E2)-induced prolactin surge in ovariectomized (OVX) female Wistar Han rats. Daily treatment with DAs over 7 days led to a reduction in the prolactin surge in E2-implanted OVX rats. Specifically, pergolide induced a significant decrease in prolactin levels at all time points compared with the OVX-E2 control group. Similarly, rotigotine dose-dependently suppressed plasma prolactin levels compared with the OVX-E2 control group. This study demonstrates the utility of the OVX rat model in evaluating the effects of DAs on the E2-induced prolactin surge. These results support the use of rotigotine, a DA with a long history of safe human use without significant endocrine-related adverse events, as a positive control at a dose level of 5.0 mg/kg/day for future nonclinical toxicity studies investigating the effects of novel DAs on reproductive hormones in rats.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"65-73"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}