Abstract

Background:

Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 μm (${\mathrm{PM}}_{2.5}$) correlates with a decrease in sperm count, but the biological mechanism remains elusive.

Objectives:

This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to ${\mathrm{PM}}_{2.5}$ exposure.

Methods:

Inhibitor $\mathrm{\kappa }\mathrm{B}$ kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient ${\mathrm{PM}}_{2.5}$ (CAP) exposure on hypothalamic inflammation, the hypothalamic–pituitary–gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models.

Results:

CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP- vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or pro-opiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP- vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count.

Discussion:

This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to ${\mathrm{PM}}_{2.5}$ exposure, providing a mechanistic insight into this emerging pathogenesis. https://doi.org/10.1289/EHP8868

中文翻译：

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PM2.5 小鼠精子发生过程中的暴露：抑制剂 κB 激酶 2 在前阿片黑皮质素神经元中的作用

摘要

背景：

流行病学研究表明，暴露于空气动力学直径小于或等于 2.5 μm 的环境细颗粒物（${\mathrm{下午}}_{2.5}$) 与精子数量减少相关，但生物学机制仍然难以捉摸。

目标：

这项研究测试了下丘脑炎症（一种新兴的病理生理介质）是否介导了附睾精子数量减少的发展，这是由于${\mathrm{下午}}_{2.5}$接触。

方法：

抑制剂$\mathrm{\kappa }\mathrm{乙}$激酶2（IKK2）在小鼠的所有神经元或下丘脑神经元的亚型中被条件性敲除。集中环境的影响${\mathrm{下午}}_{2.5}$(CAP) 暴露于下丘脑炎症、下丘脑-垂体-性腺 (HPG) 轴和这些小鼠模型的附睾精子计数。此外，为了测试下丘脑炎症是否足以减少精子的产生，我们在所有神经元或下丘脑神经元亚型中过表达组成型活性 IKK2 (IKK2ca)，并评估了这些过表达小鼠模型的下丘脑炎症、HPG 轴和精子产生。

结果：

CAP 暴露的野生型对照小鼠与过滤空气 (FA) 暴露的野生型对照小鼠相比，下丘脑炎症标志物表达较高，HPG 轴功能指标较低，附睾精子数量较低。相比之下，所有神经元中缺乏 IKK2 的 CAP 与 FA 暴露小鼠的所有这些测量结果是可比的。我们还发现，IKK2ca 仅在所有神经元或阿片黑皮质素原 (POMC) 神经元中过表达，而仅在刺鼠相关蛋白 (AgRP) 神经元中过表达，导致 HPG 轴功能指标降低和附睾精子数量减少。此外，我们发现，在 POMC 神经元中缺乏 IKK2 的 CAP 与 FA 暴露小鼠具有相当的下丘脑炎症标志物表达、相当的 HPG 轴功能指标和相当的附睾精子数量。

讨论：

该小鼠模型研究表明，POMC 神经元的 IKK2 在附睾精子数量减少中的因果作用是由于${\mathrm{下午}}_{2.5}$暴露，提供了对这种新兴发病机制的机制洞察。https://doi.org/10.1289/EHP8868