Wistar大鼠早期低剂量4-壬基酚暴露致发育性免疫毒性的性别差异及BMDL探讨

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2025-02-15 DOI:10.1016/j.tox.2025.154085

Jiuming Yan , Xiaoya Wang , Jinghua Xie , Liang Wang , Qijie Wei , Zhenchao Jia , Jinyao Chen

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引用次数: 0

摘要

壬基酚（NP）是一种广泛存在的环境内分泌干扰物，具有潜在的发育免疫毒性。本研究旨在探讨早期暴露于低剂量4-壬基酚（4-NP）对Wistar大鼠的性别特异性发育免疫毒性作用及其阈值。方法妊娠大鼠（F0代）从妊娠第6天（GD6）至出生后第90天（PND90）暴露于低剂量4-NP， F1代后代继续暴露于低剂量4-NP，直至PND42免疫系统成熟。我们评估了免疫器官发育、免疫反应、淋巴细胞亚群组成、细胞因子分泌和Th17/Treg细胞平衡作为发育免疫毒性的终点。进行基准剂量分析，探讨阈值。结果早期暴露于4-NP导致免疫反应的显著性别差异。雌性幼崽对4-NP更敏感，胸腺和脾脏重量减少，体液免疫功能抑制，自然杀伤（NK）细胞活性降低，Th17/Treg细胞比例失衡。雄鼠NK细胞活性受到抑制，体液免疫功能无明显变化。在暴露的雌雄幼鼠的脾脏中，磷酸化的STAT3、STAT5和JAK3蛋白水平升高。发育免疫毒性的最低基准剂量下限（BMDL）值雌性大鼠（以胸腺重量为基础）低于雄性大鼠（以NK细胞活性为基础）。结论早期暴露于4-NP可诱导大鼠性别特异性发育免疫毒性，雌性幼鼠表现出更大的敏感性。发育免疫毒性可作为评价4-NP风险的更敏感指标。4-NP暴露可能通过JNK/STAT通路中断Th17/Treg平衡，有待进一步研究。

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Gender difference and BMDL exploration of developmental immunotoxicity induced by early-life low-dose exposure to 4-nonylphenol in Wistar rats

Background

Nonylphenol (NP) is a widespread environmental endocrine disruptor with potential developmental immunotoxicity. The present study aimed to investigate the gender-specific developmental immunotoxic effects of early-life exposure to low doses of 4-nonylphenol (4-NP) on Wistar rats and the corresponding thresholds.

Methods

Pregnant rats (F0 generation) were exposed to low doses of 4-NP from gestational day 6 (GD6) to postnatal day 90 (PND90), and F1 offspring continued to be exposed until the maturation of the immune system on PND42. We assessed immune organ development, immune responses, lymphocyte subset composition, cytokine secretion, and the Th17/Treg cell balance as endpoints for developmental immunotoxicity. Benchmark Dose analysis was conducted to explore the thresholds.

Results

Early-life exposure to 4-NP led to significant gender-specific differences in the immune response. Female pups exhibited greater sensitivity to 4-NP, with reduced thymus and spleen weights, suppressed humoral immune function, decreased natural killer (NK) cell activity, and an imbalance in the Th17/Treg cell ratio. Male pups showed inhibition of NK cell activity but no significant changes in humoral immune function. Levels of phosphorylated STAT3, STAT5, and JAK3 proteins increased in the spleens of exposed pups of both gender. The lowest benchmark dose lower limit (BMDL) value of developmental immunotoxicity was lower in female rats (based on the thymus weight) than in male rats (based on the NK cell activity).

Conclusion

Early-life exposure to 4-NP has been shown to induce gender-specific developmental immunotoxicity in rats, with female pups exhibiting greater sensitivity. And developmental immunotoxicity may serve as a more sensitive indicator for the risk assessment of 4-NP. Th17/Treg balance may be interrupted through JNK/STAT pathway by 4-NP exposure, which needs to be further investigated.

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.