Several phthalates, mainly used as plasticizers, are known for their adverse effects on the male genital system. Previously, we demonstrated that an environmentally relevant mixture of six antiandrogenic phthalates (PMix), derived from a biomonitoring study in pregnant Brazilian women, was able to disrupt the reproductive development in male rats. Experimental groups (control, 0.1, 0.5, and 500 mg PMix/kg/day) were established starting from the extrapolated human dose (0.1 mg/kg/day), followed by doses 5 times and 5000 times higher. Pregnant rats received daily oral gavage administration of either vehicle (control) or PMix from gestational day 13 to postnatal day 10. Here, we examined male and female offspring regarding changes in gene expression of key reproductive factors in the hypothalamus and pituitary gland at adulthood and conducted a battery of behavioral tests in males, including partner preference, sexual behavior, and male attractiveness tests. PMix induced some changes in mating‐related behavior in males, as demonstrated by the absence of preference for females against males and a higher number of penetrations up to ejaculation in the 0.5 dose group. PMix decreased Esr2 expression in the male hypothalamus across all three doses, and in females at mid and high doses in both the hypothalamus and pituitary. In male hypothalamus, we also observed decreased Kiss1 transcripts in these groups and a reduction in AR at the 0.5 dose group. In summary, our results provide further evidence that phthalates in a mixture, even at low doses, may exert cumulative effects on the structures underlying sexual behavior, which seems to be more sensitive than reproductive endpoints for the same experimental design.

中文翻译：

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在子宫内和哺乳期暴露于环境相关的邻苯二甲酸盐混合物会改变大鼠的下丘脑基因表达和性偏好


几种主要用作增塑剂的邻苯二甲酸盐因其对男性生殖系统的不利影响而闻名。此前，我们证明了六种抗雄邻苯二甲酸盐 (PMix) 的环境相关混合物（源自对巴西孕妇的生物监测研究）能够扰乱雄性大鼠的生殖发育。从外推的人体剂量（0.1 mg/kg/天）开始建立实验组（对照组，0.1、0.5 和 500 mg PMix/kg/天），随后剂量增加 5 倍和 5000 倍。从妊娠第 13 天到出生后第 10 天，怀孕大鼠每天接受媒介物（对照）或 PMix 口服灌胃给药。在这里，我们检查了雄性和雌性后代成年期和成年期下丘脑和垂体中关键生殖因子基因表达的变化。对男性进行了一系列行为测试，包括伴侣偏好、性行为和男性吸引力测试。 PMix 引起了雄性交配相关行为的一些变化，如 0.5 剂量组中雌性对雄性不存在偏好以及射精前的插入次数较多所证明的那样。 PMix 在所有三种剂量下均降低了男性下丘脑中 Esr2 的表达，而在中剂量和高剂量下，PMix 降低了女性下丘脑和垂体中 Esr2 的表达。在男性下丘脑中，我们还观察到这些组中 Kiss1 转录物的减少以及 0.5 剂量组 AR 的减少。总之，我们的结果提供了进一步的证据，表明混合物中的邻苯二甲酸盐，即使是低剂量，也可能对性行为的结构产生累积影响，这似乎比相同实验设计的生殖终点更敏感。