Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale University, 60 College Street, New Haven, CT 06520-8034, USA.
Toxicol Appl Pharmacol. 2018 Jun 1;348:67-75. doi: 10.1016/j.taap.2018.04.007. Epub 2018 Apr 8.
Nonylphenol (NP) as a confirmed endocrine disrupt chemical that causes reproductive and developmental toxicity. Previous studies focused only on short-term, high-dose exposure in vivo, or in vitro on female reproductive toxicity, which cannot accurately simulate the real human exposure scenario. The present study aims to explore NP toxicity and the underlying mechanisms of chronic low-dose NP exposure (500 μg/kg·bw/day, for 8 weeks) in the reproductive system of female rats. The results indicated that NP exposure caused female reproductive toxicity, including alterations in serum 17β-estradiol (E) levels, endometria hyperplasia, altered oogenesis and significant changes in the metabolic profile observed in urine, serum, uterus and ovary. Furthermore, expression of the energy-sensitive proteins carnitine palmitoyltransferase I (CPTI), adenosine 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma (PPAR-γ) were found to be down-regulated in uterus under NP exposure, which suggested the impaired fatty acid oxidation. Accordingly, a comprehensive metabolomics study in key reproductive tissues and body fluids revealed that 12 metabolites were associated with energy metabolism as potential biomarkers for the evaluation of low toxicity at early stages, with L-carnitines being the most representative ones. The present findings provide evidence that chronic low-dose NP exposure can significantly disrupt energy homeostasis in females, thus offering further insights into NP reproductive toxicity.
壬基酚（NP）是一种已确认的内分泌干扰化学物质，会导致生殖和发育毒性。以前的研究仅集中在体内短期、高剂量暴露或体外雌性生殖毒性上，无法准确模拟真实的人类暴露情况。本研究旨在探讨慢性低剂量 NP 暴露（500μg/kg·bw/天，持续 8 周）对雌性大鼠生殖系统的毒性及其潜在机制。结果表明，NP 暴露会导致雌性生殖毒性，包括血清 17β-雌二醇（E）水平改变、子宫内膜增生、卵子发生改变以及尿液、血清、子宫和卵巢中观察到的代谢谱发生显著变化。此外，在 NP 暴露下，子宫中能量敏感蛋白肉碱棕榈酰转移酶 I（CPTI）、腺苷 5'-单磷酸激活蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体γ（PPAR-γ）的表达下调，表明脂肪酸氧化受损。因此，对关键生殖组织和体液进行的全面代谢组学研究表明，有 12 种代谢物与能量代谢相关，作为评估早期低毒性的潜在生物标志物，其中 L-肉碱最为典型。本研究结果表明，慢性低剂量 NP 暴露可显著破坏女性的能量稳态，从而进一步了解 NP 的生殖毒性。
