Background

The filaggrin gene (FLG) encodes an epidermal protein, filaggrin, which is important for normal skin barrier functions. We previously showed that FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals such as certain phthalates and parabens, suggesting increased trans-epidermal penetration. Several groups of non-persistent chemicals are suspected endocrine disrupters with potential to affect testicular function.

Objectives

To investigate associations between exposure to non-persistent chemicals and testicular function in young Danish men with and without FLG mutations.

Methods

We measured urinary concentrations of bisphenol A (BPA) and other simple phenols, parabens, and UV filters including benzophenones (BP-1, BP-3 and 4-HBP) in men genotyped for FLG R501X, 2282del4, and R2447X loss-of-function mutations; in total 65 mutation carriers and 130 non-carriers (controls) were included. Outcomes were markers of testicular function, assessed by serum reproductive hormones and semen quality.

Results

We found that associations between urinary chemical concentrations and outcomes were different in cases and controls. Within the group of FLG mutation carriers, higher urinary concentrations of BPA, BP-1 and BP-3 were associated with higher testosterone and estradiol serum levels and lower FSH. Similar trends in hormone levels were observed for FLG mutation carriers with measurable levels of 4-HBP compared to those who had no detectable levels of urinary 4-HBP. Furthermore, those in the highest urinary BPA quartile had lower sperm motility than those in the lower quartiles. None of these associations were evident in the control group. In the control group, however, lower sperm motility and sperm concentration were observed in the men with detectable urinary 4-HBP compared to the men non-detectable urinary 4-HBP. We found no association between any parabens and outcomes, nor for the other measured phenols or UV filters.

Conclusions

Associations between male reproductive health parameters and urinary levels of BPA and benzophenones such as BP-3, BP-1 and 4-HBP were observed in FLG mutation carriers but not in controls from the same study population. This difference between FLG mutation carriers and non-carriers is not explained solely by differences in exposure levels of the examined compounds as e.g. BPA and 4-HBP urinary levels did not differ between the two groups. We hypothesise that effects of exposure to these compounds may be modulated in FLG mutation carriers by either different levels of co-exposures or by route of uptake, with a higher fraction of the uptake by dermal uptake.

中文翻译：

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年轻人中尿液中苯酚，对羟基苯甲酸酯和二苯甲酮的排泄：与生殖激素和精液质量的关联因Filaggrin基因的突变而改变

背景

丝蛋白基因（FLG）编码一种表皮蛋白丝蛋白，该蛋白对于正常的皮肤屏障功能很重要。我们以前表明，FLG功能丧失的突变携带者对某些非持久性化学物质（例如某些邻苯二甲酸酯和对羟基苯甲酸酯）的内部暴露较高，表明经表皮渗透增加。几类非持久性化学物质被怀疑是可能影响睾丸功能的内分泌干扰物。

目标

调查有和没有FLG突变的年轻丹麦男性接触非持久性化学物质与睾丸功能之间的关联。

方法

我们在针对FLG R501X，2282del4和R2447X基因型分型的男性中测量了双酚A（BPA）和其他简单的酚，对羟基苯甲酸酯和紫外线过滤剂（包括二苯甲酮（BP-1，BP-3和4-HBP））的尿液浓度功能突变；总共包括65个突变携带者和130个非携带者（对照）。结果是睾丸功能的标志物，通过血清生殖激素和精液质量进行评估。

结果

我们发现，在病例和对照中，尿中化学物质浓度与结局之间的关联是不同的。在FLG突变携带者组中，较高的尿液中BPA，BP-1和BP-3与较高的睾丸激素和雌二醇血清水平以及较低的FSH有关。对于FLG，观察到激素水平的相似趋势与未检测到尿液4-HBP水平的突变携带者相比，具有可测量的4-HBP水平的突变携带者。此外，尿液中BPA最高的四分之一患者的精子活力比较低的四分之一的患者低。这些关联在对照组中均不明显。然而，在对照组中，与检测不到尿液4-HBP的男性相比，检测到尿液4-HBP的男性的精子活力和精子浓度较低。我们没有发现任何对羟基苯甲酸酯和结果之间的关联，也没有发现其他测定的苯酚或紫外线过滤剂。

结论

在FLG突变携带者中观察到男性生殖健康参数与尿液中BPA和二苯甲酮（如BP-3，BP-1和4-HBP）之间的关联，但在同一研究人群的对照组中未观察到。FLG突变携带者和非携带者之间的这种差异不能仅通过所检查化合物的暴露水平差异来解释，例如两组之间的BPA和4-HBP尿液水平没有差异。我们假设，暴露于这些化合物的影响可能在FLG突变携带者中通过不同程度的共同暴露或通过摄取途径来调节，其中较高比例的摄取是通过皮肤摄取。