Reproductive toxicology最新文献_第5页

Association between dietary intake estimated levels of PCDD/Fs and human sperm quality 饮食摄入PCDD/Fs估计水平与人类精子质量之间的关系。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-09 DOI: 10.1016/j.reprotox.2025.108831

María Ángeles Martínez , Albert Salas-Huetos , María Fernández de la Puente , Cristina Valle-Hita , Nadine Khoury , Elena Sánchez-Resino , Carla Ramos-Rodríguez , Estefanía Davila-Cordova , Jordi Salas-Salvadó , Nancy Babio

This study aimed to investigate the association between estimated dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and human sperm quality. This study cross-sectionally assessed the associations between estimated dietary intake of PCDD/Fs and sperm quality parameters in 200 participants aged 18–40 years from the Led-Fertyl study. Linear regression models, accounting for potential confounding variables, were employed to evaluate the relationships. To estimate the PCDD/Fs exposure, food frequency questionnaires and the latest data on PCDD/Fs concentrations in food, primarily from Spanish sources, were used. Our findings indicate that, in comparison to participants in the lowest tertile, those in the highest tertile (T3) of PCDD/Fs dietary intake exhibited significantly elevated body mass index, increased consumption of meat, fish and eggs, and decreased consumption of nuts. Furthermore, individuals in T3 demonstrated a higher percentage of sperm head abnormalities (4.65 % [0.10; 9.24]; p-trend= 0.037) and a corresponding increase per 1-SD increment in energy-adjusted total PCDD/Fs dietary intake (1.84 % [0.38; 3.68]). No significant associations for other sperm parameters were found. Minimal research exists on PCDD/F dietary exposure and human sperm quality. This study shows significant direct association between higher PCDD/Fs intake and the percentage of sperm head abnormalities which potentially may compromise human reproductive health.

本研究旨在探讨多氯二苯并对二恶英（PCDDs）和多氯二苯并呋喃（PCDFs）的估计膳食摄入量与人类精子质量之间的关系。本研究横断面评估了200名年龄在18-40岁的铅-铁研究参与者中PCDD/Fs的估计饮食摄入量与精子质量参数之间的关系。考虑潜在混杂变量的线性回归模型被用来评估这些关系。为了估计PCDD/Fs暴露，使用了食物频率问卷和食品中PCDD/Fs浓度的最新数据，这些数据主要来自西班牙。我们的研究结果表明，与最低分位的参与者相比，最高分位（T3）饮食摄入PCDD/Fs的参与者表现出显著的体重指数升高，肉、鱼和蛋的消费量增加，坚果的消费量减少。此外，T3组的个体显示出更高的精子头畸形百分比(4.65% [0.10；9.24);p-trend= 0.037)，每增加1 sd，能量调整后的总PCDD/Fs日粮摄入量相应增加(1.84% [0.38；3.68])。没有发现其他精子参数的显著关联。关于PCDD/F饮食暴露与人类精子质量的研究很少。这项研究表明，较高的PCDD/Fs摄入量与精子头部异常百分比之间存在显著的直接关联，这可能会损害人类生殖健康。

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引用次数: 0

Humanin alone and in combination with GnRHa therapy attenuates ovarian dysfunction induced by prepubertal cyclophosphamide chemotherapy in female mice 人源素单用和联合GnRHa治疗可减轻雌性小鼠青春期前环磷酰胺化疗引起的卵巢功能障碍。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-08 DOI: 10.1016/j.reprotox.2024.108824

Liu Liu , Huawei Wang , Wen Wen, Shunqing Wang, Liqin Zuo, Yulin Cheng, Meng Rao, Yuru Ma, Li Tang

Prepubertal chemotherapy induced ovarian damage poses a significant threat to female fertility, particularly following cyclophosphamide (CP) treatment. Humanin (HNG), a small molecule polypeptide encoded by mitochondrial DNA, has a variety of effects, this study aimed to investigate the protective effects of HNG and its combination with conventional Gonadotropin Releasing Hormone Agonist (GnRHa) on ovarian function in a CP-induced damage model. The 21-day-old C57BL/6 J female mice were randomly assigned to six groups: Control, CP model, HNG, HNG+CP, GnRHa+CP, and HNG+GnRHa+CP. Reproductive related parameters were assessed through histopathological examination, follicle counts, serum sex hormone levels, estrous cycle monitoring, and oxidative stress evaluation. Results indicated that CP treatment led to significant reproductive dysfunction especially ovarian dysfunction, evidenced by reduced follicles, hormonal imbalances, prolonged estrous cycles, reduced body weight, and diminished ovarian and uterine weights, alongside pathological alterations. Notably, HNG treatment, both alone and in conjunction with GnRHa, significantly mitigated these adverse effects, however the combination did not provide additional benefits over HNG alone regarding follicles preservation and antioxidant capacity. Transcriptomic analysis revealed significant enrichment in inflammation and immune response pathways following HNG treatment. In conclusion, HNG demonstrates potential as a therapeutic agent to protect against CP-induced ovarian damage, offering insights for future strategies aimed at preserving female fertility during chemotherapy.

青春期前化疗引起的卵巢损伤对女性生育能力构成重大威胁，特别是在环磷酰胺（CP）治疗后。Humanin （HNG）是一种由线粒体DNA编码的小分子多肽，具有多种作用，本研究旨在探讨HNG及其与常规促性腺激素释放激素激动剂（GnRHa）联合使用对cp损伤模型卵巢功能的保护作用。将21日龄C57BL/6J雌性小鼠随机分为对照组、CP模型组、HNG组、HNG+CP组、GnRHa+CP组和HNG+GnRHa+CP组。通过组织病理学检查、卵泡计数、血清性激素水平、发情周期监测和氧化应激评估来评估卵巢功能。结果表明，CP治疗导致明显的生殖功能障碍，尤其是卵巢功能障碍，表现为卵泡减少、激素失衡、发情周期延长、体重减轻、卵巢和子宫重量减少，并伴有病理改变。值得注意的是，HNG治疗，无论是单独治疗还是与GnRHa联合治疗，都显著减轻了这些不良反应，然而，在卵泡保存和抗氧化能力方面，联合治疗并没有比HNG单独治疗提供更多的益处。转录组学分析显示，HNG治疗后炎症和免疫反应通路显著富集。总之，HNG显示了作为一种治疗药物的潜力，可以防止cp诱导的卵巢损伤，为未来在化疗期间保护女性生育能力的策略提供见解。

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引用次数: 0

Adrenomedullin gene delivery rescues estrogen production in Leydig cells via the inhibition of TGF-β1/Smads signaling pathway 肾上腺髓质素基因传递通过抑制TGF-β1/Smads信号通路恢复间质细胞雌激素的产生。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-08 DOI: 10.1016/j.reprotox.2025.108834

You-wen Luo , Xia-lian Zhu , Zhi-min Yang , Jian-hua Zhou , Tong Tao , Bing-hai Chen , Song-lin Qin , Bo-long Liu , Wei Hu

Our previous findings demonstrated that adrenomedullin (ADM) protects against the reduction in testosterone production and apoptosis of Leydig cells both in vitro and in vivo. In this study, we investigated whether ADM could preserve estrogen production in Leydig cells by suppressing the transforming growth factor-β1 (TGF-β1) / Smads signaling pathway. Leydig cells were treated with lipopolysaccharide (LPS) and recombinant adenovirus ADM (Ad-ADM), an adeno-associated viral vector expressing ADM. Cell viability and cytochrome P450 aromatase (P450arom) activity were assessed. Estrogen, testosterone, and TGF-β1 concentrations in the culture medium were measured. Additionally, the gene expression and protein levels of CYP19, TGF-β1, and Smads were evaluated. The results indicated that Ad-ADM mitigated the reductions in Leydig cell viability and testosterone production, counteracted the decreases in P450arom activity, and restored CYP19 gene expression and protein levels in LPS-treated cells. Moreover, Ad-ADM reduced the elevated gene expression and protein levels of Smads and TGF-β1 induced by LPS. Based on these findings, we propose that ADM safeguards estrogen production in Leydig cells by inhibiting the TGF-β1/Smads signaling pathway.

我们之前的研究结果表明，肾上腺髓质素（ADM）在体外和体内都能防止睾丸激素分泌减少和间质细胞凋亡。在本研究中，我们研究了ADM是否通过抑制转化生长因子-β1 (TGF-β1) / Smads信号通路来维持间质细胞雌激素的产生。用脂多糖（LPS）和重组腺病毒ADM (Ad-ADM)（一种表达ADM的腺相关病毒载体）处理间质细胞，测定细胞活力和细胞色素P450芳香化酶（P450arom）活性。测定培养基中雌激素、睾酮和TGF-β1的浓度。检测CYP19、TGF-β1、Smads的基因表达及蛋白水平。结果表明，Ad-ADM减轻了间质细胞活力和睾酮产生的下降，抵消了P450arom活性的下降，恢复了lps处理细胞中CYP19基因的表达和蛋白水平。此外，Ad-ADM降低了LPS诱导的Smads和TGF-β1基因表达和蛋白水平升高。基于这些发现，我们提出ADM通过抑制TGF-β1/Smads信号通路来保护间质细胞雌激素的产生。

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引用次数: 0

Ampligo® 150 ZC affect the expression of sex hormone receptors and cell proliferation marker in female rabbit ovary: Protective effects of thyme essential oil and vitamin C Ampligo®150 ZC对兔卵巢性激素受体和细胞增殖标志物表达的影响：百里香精油和维生素C的保护作用

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-07 DOI: 10.1016/j.reprotox.2025.108833

Chahrazed Makhlouf , Hassina Khaldoun , Louisa Béchohra , Nacima Djennane , Amina Settar , Dalila Tarzaali , Yasmine Oularbi , Smail Krabi , Soumya Bokreta , Nacira Zerrouki Daoudi

Pesticides tend to cause serious reproductive defects, disturbing endocrine functions and reducing fertility, especially in females. The objective of this work was to identify the reprotoxic effects of Ampligo® 150 ZC (AP), a mixture formulation of lambda cyhalothrin and chlorantraniliprole, on the ovary of female rabbits (Oryctolagus cuniculus) and the possible protective effect of co-treatment with thyme essential oil (TEO), extracted from (Thymus vulgaris) species, and vitamin C (vit C). Twenty female rabbits were divided into four equal groups (n = 5): Control (distilled water), AP (20 mg/ kg bw of the insecticide mixture every other day, by gavage for 28 days), AP+TEO (20 mg/ kg bw of AP + 0.5 mg/ kg bw of TEO every other day), and AP+TEO+Vit C (20 mg/ kg bw of AP + 0.5 mg/ kg bw of TEO + 200 mg/ kg bw of vitamin C every other day). The effects were tested on body weight, ovary histomorphometry, and immunohistochemical expression of AFP, estrogen receptor (ER), and progesterone receptor (PR). The results revealed that AP decreased body and ovarian weights, caused ovarian histological damages, and increased collagen fiber deposition. The immunostaining of the ovary showed a significant (p < .001) increase in AFP and decrease in both ER and PR expressions. In the opposite, co-administration of TEO and vitamin C was effective in improving all caused alterations. In conclusion, combined use of TEO and vitamin C ameliorated the toxic effects of Ampligo® on the ovary in female rabbits.

农药容易造成严重的生殖缺陷，干扰内分泌功能，降低生育能力，尤其是对女性。本研究旨在研究高效氯氟氰菊酯和氯虫腈混合制剂Ampligo®150 ZC （AP）对雌性兔卵巢的生殖毒性作用，以及百里香精油（TEO）和维生素C （vit C）共同作用对雌性兔卵巢的保护作用。20只雌性兔随机分为4组（n=5）：对照（蒸馏水）、AP（每隔一天给药20mg/ kg bw，连续灌胃28 d）、AP+TEO（每隔一天给药20mg/ kg bw +TEO 0.5mg/ kg bw）、AP+TEO+维生素C（每隔一天给药20mg/ kg bw +TEO 0.5mg/ kg bw +维生素C 200mg/ kg bw）。测定小鼠体重、卵巢组织形态学及AFP、雌激素受体（ER）、孕激素受体（PR）的免疫组化表达。结果显示，AP降低了机体和卵巢重量，造成卵巢组织损伤，增加了胶原纤维沉积。卵巢免疫染色显示明显的(p

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引用次数: 0

The mechanisms of tripterygium glycosides-induced reproductive toxicity and detoxification strategies 雷公藤多苷诱导生殖毒性的机制及解毒策略。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-06 DOI: 10.1016/j.reprotox.2025.108830

Zechen Niu , Huanhuan Zhang , Chunzhou Cai , Ting Yang , Tian Ma , Dingqiao Xu , Dongxiao Cui , Yuping Tang

Tripterygium glycosides (TG) is a widely used preparation in the treatment of rheumatoid arthritis (RA), nephrotic syndrome and diabetic nephropathy. Although the clinical efficacy is definite, the side-effects on reproductive system limit its wide application. It is of great significance to take measures to alleviate its reproductive toxicity and expand its clinical use. The mechanism of TG-induced reproductive toxicity involves oxidative stress, inflammation, apoptosis, and metabolism imbalance, which lead to adverse effects on male and female reproductive organs. To mitigate these effects, detoxification strategies including combining TG with other agents have been proved to counteract its toxicity. This review will provide information for the studies of TG-induced reproductive toxicity, and also provide insights for developing novel strategies to alleviate the reproductive side effects of TG.

雷公藤多苷（TG）是一种广泛用于治疗类风湿性关节炎（RA）、肾病综合征和糖尿病肾病的制剂。虽然临床疗效明确，但对生殖系统的不良反应限制了其广泛应用。采取措施减轻其生殖毒性，扩大其临床应用具有重要意义。tg诱导生殖毒性的机制涉及氧化应激、炎症、细胞凋亡和代谢失衡等，对雌雄生殖器官产生不良影响。为了减轻这些影响，包括将TG与其他药物结合在内的解毒策略已被证明可以抵消其毒性。本文综述将为TG诱导生殖毒性的研究提供信息，并为开发新的策略来减轻TG的生殖副作用提供见解。

引用次数: 0

Exploring the impact of environmental factors on male reproductive health through epigenetics 从表观遗传学角度探讨环境因素对男性生殖健康的影响。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-06 DOI: 10.1016/j.reprotox.2025.108832

Yi Zhang , Jing-Yan Song , Zhen-Gao Sun

Male infertility has become an increasingly severe global health issue, with its incidence significantly rising over the past few decades. This paper delves into the crucial role of epigenetics in male reproductive health, focusing particularly on the effects of DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs regulation on spermatogenesis. Exposure to various environmental factors can cause sperm DNA damage, leading to epigenetic abnormalities. Among these factors, we have discussed heavy metals (including Zinc, Cadmium, Arsenic, Copper), phthalates, electromagnetic radiation, and temperature in detail. Notably, aberrations in DNA methylation are closely associated with various symptoms of male infertility, and histone modifications and chromatin remodeling are essential for sperm maturation and function. By synthesizing existing literature and experimental data, this narrative review investigates how environmental factors influence male reproductive health through epigenetic mechanisms, thus providing new theoretical foundations and practical guidelines for the early diagnosis and treatment of male infertility.

男性不育已成为一个日益严重的全球健康问题，其发病率在过去几十年中显著上升。本文深入探讨了表观遗传学在男性生殖健康中的重要作用，重点介绍了DNA甲基化、组蛋白修饰、染色质重塑和非编码rna调控对精子发生的影响。暴露于各种环境因素会导致精子DNA损伤，导致表观遗传异常。在这些因素中，我们详细讨论了重金属（包括锌、镉、砷、铜）、邻苯二甲酸盐、电磁辐射和温度。值得注意的是，DNA甲基化异常与男性不育的各种症状密切相关，组蛋白修饰和染色质重塑对精子成熟和功能至关重要。本文综合现有文献和实验数据，探讨环境因素如何通过表观遗传机制影响男性生殖健康，为男性不育症的早期诊断和治疗提供新的理论基础和实践指导。

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引用次数: 0

Analyzing high-throughput assay data to advance the rapid screening of environmental chemicals for human reproductive toxicity 分析高通量检测数据，推进环境化学品对人类生殖毒性的快速筛查。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.reprotox.2024.108725

Julia R. Varshavsky , Juleen Lam , Courtney Cooper , Patrick Allard , Jennifer Fung , Ashwini Oke , Ravinder Kumar , Joshua F. Robinson , Tracey J. Woodruff

While high-throughput (HTP) assays have been proposed as platforms to rapidly assess reproductive toxicity, there is currently a lack of established assays that specifically address germline development/function and fertility. We assessed the applicability domains of yeast (S. cerevisiae) and nematode (C. elegans) HTP assays in toxicity screening of 124 environmental chemicals, determining their agreement in identifying toxicants and their concordance with reproductive toxicity in vivo. We integrated data generated in the two models and compared results using a streamlined, semi-automated benchmark dose (BMD) modeling approach. We then extracted and modeled relevant mammalian in vivo data available for the matching chemicals included in the Toxicological Reference Database (ToxRefDB). We ranked potencies of common compounds using the BMD and evaluated correlation between the datasets using Pearson and Spearman correlation coefficients. We found moderate to good correlation across the three data sets, with r = 0.48 (95 % CI: 0.28–1.00, p<0.001) and r_s = 0.40 (p=0.002) for the parametric and rank order correlations between the HTP BMDs; r = 0.95 (95 % CI: 0.76–1.00, p=0.0005) and r_s = 0.89 (p=0.006) between the yeast assay and ToxRefDB BMDs; and r = 0.81 (95 % CI: 0.28–1.00, p=0.014) and r_s = 0.75 (p=0.033) between the worm assay and ToxRefDB BMDs. Our findings underscore the potential of these HTP assays to identify environmental chemicals that exhibit reproductive toxicity. Integrating these HTP datasets into mammalian in vivo prediction models using machine learning methods could further enhance their predictive value in future rapid screening efforts.

虽然高通量（HTP）测定法已被提出作为快速评估生殖毒性的平台，但目前还缺乏专门针对生殖系发育/功能和生育能力的成熟测定法。我们评估了酵母（S. cerevisiae）和线虫（C. elegans）HTP 试验在 124 种环境化学物质毒性筛选中的适用领域，确定了它们在识别毒性物质方面的一致性以及与体内生殖毒性的一致性。我们整合了两种模型中生成的数据，并使用简化、半自动化的基准剂量 (BMD) 建模方法对结果进行了比较。然后，我们提取了毒理学参考数据库（ToxRefDB）中与之匹配的化学物质的相关哺乳动物体内数据，并建立了模型。我们使用 BMD 对常见化合物的效力进行了排序，并使用皮尔逊和斯皮尔曼相关系数评估了数据集之间的相关性。我们发现三个数据集之间存在中度到良好的相关性，HTP BMDs 之间的参数相关性和排序相关性分别为 r = 0.48（95 % CI：0.28-1.00，ps = 0.40（p=0.002）；r = 0.95（95 % CI：0.76-1.00，p=0.0005）和 rs = 0.89（p=0.006）；酵母检测和 ToxRefDB BMDs 之间的 r = 0.81（95 % CI：0.28-1.00，p=0.014）和 rs = 0.75（p=0.033）。我们的研究结果强调了这些 HTP 检测方法在识别具有生殖毒性的环境化学品方面的潜力。利用机器学习方法将这些 HTP 数据集整合到哺乳动物体内预测模型中，可以进一步提高它们在未来快速筛选工作中的预测价值。

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引用次数: 0

Mixed exposure to PFOA and PFOS induces oocyte apoptosis and subfertility in mice by activating the Hippo signaling pathway PFOA和PFOS混合暴露通过激活Hippo信号通路诱导小鼠卵母细胞凋亡和低生育能力。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2024-12-31 DOI: 10.1016/j.reprotox.2024.108829

Xiang-Zhu Yan , Jia Peng , Yu-Qing Liu , Ruo-Nan Fan , Xin-Yi Ni , Ling Gong , Dan-Ni Zhang , Xin Huang , Shu-Hua Tan , Hai-Long Wang

Per- and polyfluoroalkyl substances (PFAS) are synthetic perfluorinated compounds known for their persistence in the environment and reproduction toxicity. PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), have been identified in the follicular fluid of infertile women. However, the specific of PFOA and PFOS mixture on oocyte quality and female fertility remain unclear. In this study, we exposed female mice to combination of PFOA and PFOS to investigate the underlying mechanisms impairing fertility and oocyte maturation. Our results showed that exposure to the mixture induced epigenetic alterations and DNA damage in oocytes, impairing meiosis. Additionally, mitochondrial dysfunction caused by the exposure to the mixture led to oxidative stress and apoptosis in the oocytes. The reduction in oocyte quality resulted in a decrease in blastocyst quality and litter size. Furthermore, single-cell transcriptome analysis indicated that exposure to the mixture disrupted energy metabolism and triggered apoptosis, possibly through the activation of the Hippo signaling pathway. Overall, our results suggest that exposure to PFOA and PFOS mixture impairs the fertility in mice through the activation of the Hippo signaling pathway-induced oocytes apoptosis.

全氟烷基和多氟烷基物质（PFAS）是合成的全氟化合物，已知其在环境中具有持久性和生殖毒性。在不孕妇女的卵泡液中发现了全氟辛烷酸（PFOA）和全氟辛烷磺酸（PFOS）。然而，PFOA和PFOS混合物对卵母细胞质量和女性生育能力的特异性尚不清楚。在这项研究中，我们将雌性小鼠暴露于PFOA和PFOS的组合中，以研究损害生育能力和卵母细胞成熟的潜在机制。我们的研究结果表明，暴露于混合物诱导卵母细胞的表观遗传改变和DNA损伤，损害减数分裂。此外，暴露于混合物引起的线粒体功能障碍导致卵母细胞氧化应激和凋亡。卵母细胞质量的降低导致囊胚质量和产仔数的下降。此外，单细胞转录组分析表明，暴露于这种混合物中可能通过激活Hippo信号通路破坏能量代谢并引发细胞凋亡。总之，我们的研究结果表明，暴露于PFOA和PFOS混合物通过激活Hippo信号通路诱导的卵母细胞凋亡来损害小鼠的生育能力。

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引用次数: 0

Perfluoroalkyl substances (PFAS) exposure and preeclampsia risk: Impaired angiogenesis through suppression of VEGF signaling 全氟烷基物质（PFAS）暴露与子痫前期风险：通过抑制VEGF信号抑制血管生成

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2024-12-26 DOI: 10.1016/j.reprotox.2024.108827

Jay S. Mishra , Bradley Bosse , Kara K. Hoppe , Kristen Malecki , Scott J. Hetzel , Sathish Kumar

Per- and polyfluoroalkyl substances (PFAS) are linked to preeclampsia (PE), a condition involving abnormal angiogenesis. Prior research on this association has been inconclusive. We investigated the relationship between maternal PFAS exposure and PE risk in Wisconsin. We also examined if PFAS disrupts angiogenesis and, if so, what mechanisms are involved. We conducted a case-control study with 40 PE cases and 40 controls. Maternal serum was analyzed for 38 different PFAS compounds using LC MS/MS. Functional in vitro experiments assessed PFOS effects on angiogenesis and mechanisms. Maternal serum samples from women with PE exhibited significantly higher PFOS and PFHPS concentrations than controls. After adjusting for confounders, each log-scale IQR increase in PFOS and PFHPS concentrations was associated with a 7.18-fold (95 % CI: 2.24, 23.0) and 5.40-fold (95 % CI: 1.81, 16.1) higher odds of PE, respectively. Furthermore, PFOS and PFHPS were positively associated with sFLT1 levels and the sFLT1/PLGF ratio. In vitro experiments revealed that PFOS exposure impaired HUVEC proliferation, migration, and tube formation, essential processes for angiogenesis. The membrane-based antibody array showed that PFOS decreased expression of multiple angiogenic proteins, including I-TAC, uPAR, VEGFR2, MMP-1, IL-1α, Angiopoietin-2, IL-1β, PECAM-1, TIE-2, and TIMP-2. The qPCR analysis demonstrated that PFOS decreased VEGFR2, the upstream target of VEGF, at the transcriptional level. In conclusion, elevated PFAS, especially PFOS and PFHPS, are linked to increased PE risk. PFOS may suppress angiogenesis via attenuated VEGFR2-mediated signaling, providing a molecular mechanism linking PFAS and PE pathogenesis.

全氟烷基和多氟烷基物质（PFAS）与子痫前期（PE）有关，这是一种涉及血管生成异常的疾病。先前对这一关联的研究尚无定论。我们调查了威斯康星州母亲PFAS暴露与PE风险之间的关系。我们还研究了PFAS是否会破坏血管生成，如果是，涉及什么机制。我们对40例PE病例和40例对照进行了病例-对照研究。采用LC - MS/MS对母体血清中38种不同的PFAS化合物进行分析。体外功能实验评估全氟辛烷磺酸对血管生成的影响及其机制。PE妇女的母体血清样本显示PFOS和PFHPS浓度明显高于对照组。在调整混杂因素后，PFOS和PFHPS浓度每增加一个对数尺度IQR分别与7.18倍（95% CI: 2.24, 23.0）和5.40倍（95% CI: 1.81, 16.1）高PE几率相关。此外，PFOS和PFHPS与sFLT1水平和sFLT1/PLGF比值呈正相关。体外实验显示，全氟辛烷磺酸暴露会损害HUVEC的增殖、迁移和管形成，这是血管生成的基本过程。膜基抗体阵列显示，PFOS降低了多种血管生成蛋白的表达，包括I-TAC、uPAR、VEGFR2、MMP-1、IL-1α、Angiopoietin-2、IL-1β、PECAM-1、TIE-2和TIMP-2。qPCR分析表明，PFOS在转录水平上降低了VEGF的上游靶点VEGFR2。总之，PFAS升高，尤其是PFOS和PFHPS，与PE风险增加有关。PFOS可能通过vegfr2介导的信号减弱抑制血管生成，提供了PFAS与PE发病机制之间的分子机制。

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引用次数: 0

Computational insights into maternal environmental pollutants and folate pathway regulation 计算洞察母体环境污染物和叶酸途径调节。

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2024-12-26 DOI: 10.1016/j.reprotox.2024.108825

Adarsh Kumar Shukla, Shadab Ahamad, Prachi Kukshal

Exposure to environmental pollutants during pregnancy can adversely affect fetal growth and postnatal development. While numerous studies have explored the interaction between environmental toxic chemicals and the folate pathway, few have examined their inhibitory effects on key targets. This computational study identified 27 maternal environmental toxicants using the Comparative Toxicogenomics Database (CTD) and analyzed them to identify their targets. Molecular modeling, docking, and dynamics simulations revealed that folate receptors (FOLR1, FOLR2, and FOLR3) and transporters (SLC19A1 and SLC46) are major targets. Among these, FOLR3 exhibited the strongest interactions with toxicants such as Dichlorodiphenyltrichloroethane (DDT), Bisphenols, Dioxin, and other investigated toxicants. Toxicity profiling showed that even minimal exposure to these pollutants significantly impacts maternal health and disrupts folate metabolism, leading to fetal malformations. This study highlights the critical role of maternal toxicants in hindering the folate pathway, with severe implications for fetal development.

怀孕期间暴露于环境污染物会对胎儿生长和产后发育产生不利影响。虽然许多研究已经探索了环境有毒化学物质与叶酸途径之间的相互作用，但很少有人研究它们对关键靶点的抑制作用。本计算研究使用比较毒物基因组数据库（CTD）确定了27种母体环境毒物，并对其进行分析以确定其目标。分子模型、对接和动力学模拟显示叶酸受体（FOLR1、FOLR2和FOLR3）和转运体（SLC19A1和SLC46）是主要靶点。其中，FOLR3与二氯二苯三氯乙烷（DDT）、双酚类、二恶英和其他研究毒物的相互作用最强。毒性分析表明，即使最低限度地接触这些污染物也会严重影响孕产妇健康，破坏叶酸代谢，导致胎儿畸形。这项研究强调了母体有毒物质在阻碍叶酸通路中的关键作用，对胎儿发育有严重影响。

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引用次数: 0