Exposure of Adult Female Mice to Low Doses of di(2-ethylhexyl) Phthalate Alone or in an Environmental Phthalate Mixture: Evaluation of Reproductive Behavior and Underlying Neural Mechanisms,Environmental Health Perspectives

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Exposure of Adult Female Mice to Low Doses of di(2-ethylhexyl) Phthalate Alone or in an Environmental Phthalate Mixture: Evaluation of Reproductive Behavior and Underlying Neural Mechanisms
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2021-1-27 , DOI: 10.1289/ehp7662
Nolwenn Adam ₁ , Linda Brusamonti ₁ , Sakina Mhaouty-Kodja ₁

Affiliation

Abstract

Background:

We have previously shown that adult male mice exposure to low doses of an ubiquitous endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP), alters courtship behavior.

Objective:

The effects of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on estrous cyclicity, reproductive behavior, and underlying neural structures were analyzed in female mice.

Methods:

Two-month-old C57BL/6J females were exposed orally for 6 wk to DEHP alone (0, 5 or $50 micrograms per kilogram per day$ ) or to DEHP ( $5 micrograms per kilogram per day$ ) in a phthalate mixture. Estrous cyclicity was analyzed in intact mice, and behavior [lordosis, olfactory preference, partner preference, ability to stimulate male ultrasonic vocalizations (USVs)] was measured in ovariectomized mice primed with estradiol and progesterone. Immunohistochemical studies were conducted in the neural structures involved in behavior for estrogen receptor (ER) $α$ and progesterone receptor (PR).

Results:

Exposure to DEHP alone or in mixture lengthened the estrous cycle duration, with a shorter proestrus and longer estrus and metestrus stages. Under normalized hormonal levels, females exposed to DEHP alone or in mixture exhibited altered olfactory preference. A lower lordosis behavior and ability to attract and stimulate male emission of courtship USVs was observed, probably due to modifications of pheromonal emission in exposed females. The behavioral alterations were associated with a lower number of PR-expressing neurons, without changes in $ER α$ , in the neural circuitry underlying sexual behavior. The majority of effects observed was comparable between the two DEHP doses and were driven by DEHP in the mixture.

Conclusions:

Exposure to environmental doses of DEHP alone or in mixture altered several components of female sexual behavior in mice, probably through selective disruption of neural PR signaling. Together with the previously reported vulnerability of male mice, this finding suggests a major impact of exposure to phthalates on sexual reproduction, including in other species with similar neural regulatory processes. https://doi.org/10.1289/EHP7662

中文翻译：

成年雌性小鼠单独或在环境邻苯二甲酸酯混合物中暴露于低剂量的二（2-乙基己基）邻苯二甲酸酯：生殖行为和潜在神经机制的评估

摘要

背景：

我们之前已经表明，成年雄性小鼠接触低剂量的无处不在的内分泌干扰物邻苯二甲酸二（2-乙基己基）酯 (DEHP)，会改变求偶行为。

客观的：

在雌性小鼠中分析了成人单独接触低剂量 DEHP 或环境邻苯二甲酸酯混合物中对发情周期、生殖行为和潜在神经结构的影响。

方法：

两个月大的 C57BL/6J 雌性仅口服暴露于 DEHP（0、5 或 $50 micrograms per kilogram per day$ ) 或 DEHP ( $5 micrograms per kilogram per day$ ) 在邻苯二甲酸盐混合物中。在完整小鼠中分析发情周期，并在用雌二醇和孕酮致敏的去卵巢小鼠中测量行为 [脊柱前凸、嗅觉偏好、伴侣偏好、刺激雄性超声发声 (USV) 的能力]。在涉及雌激素受体 (ER) 行为的神经结构中进行免疫组织化学研究 $α$ 和孕激素受体 (PR)。

结果：

单独或混合暴露于 DEHP 会延长发情周期持续时间，发情前期较短，发情和发情阶段较长。在标准化的荷尔蒙水平下，单独或混合接触 DEHP 的雌性表现出嗅觉偏好的改变。观察到较低的前凸行为以及吸引和刺激求偶 USV 的雄性发射的能力，可能是由于暴露的雌性中信息素发射的改变。行为改变与表达 PR 的神经元数量减少有关，而 $急诊室 α$ ，在潜在性行为的神经回路中。观察到的大多数效果在两种 DEHP 剂量之间具有可比性，并且是由混合物中的 DEHP 驱动的。