Urinary excretion of phenols, parabens and benzophenones in young men: Associations to reproductive hormones and semen quality are modified by mutations in the Filaggrin gene

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. Keywords: Endocrine disrupting chemicals, Bisphenol A, Benzophenone-3, Testicular function, Filaggrin gene