title: Associations of filaggrin gene loss-of-function variants with urinary phthalate metabolites and testicular function in young Danish Men.
abstract: BACKGROUND
  Filaggrin is an epidermal protein that is crucial for skin barrier function. Up to 10% of Europeans and 5% of Asians carry at least one null allele in the filaggrin gene (FLG). Reduced expression of filaggrin in carriers of the null allele is associated with facilitated transfer of allergens across the epidermis. We hypothesized that these individuals may have increased transdermal uptake of endocrine disruptors, including phthalates.
  
  
  OBJECTIVE
  We investigated urinary excretion of phthalate metabolites and testicular function in young men with and without FLG loss-of-function variants in a cross-sectional study of 861 young men from the general Danish population.
  
  
  METHODS
  All men were genotyped for FLG R501X, 2282del4, and R2447X loss-of-function variants. We measured urinary concentrations of 14 phthalate metabolites and serum levels of reproductive hormones. We also evaluated semen quality.
  
  
  RESULTS
  Sixty-five men (7.5%) carried at least one FLG-null allele. FLG-null carriers had significantly higher urinary concentrations of several phthalate metabolites, including a 33% higher concentration of MnBP (mono-n-butyl phthalate; 95% CI: 16, 51%). FLG-null variants were not significantly associated with reproductive hormones or semen quality parameters.
  
  
  CONCLUSIONS
  This study provides evidence that carriers of FLG loss-of-function alleles may have higher internal exposure to phthalates, possibly due to increased transepidermal absorption. FLG loss-of-function variants may indicate susceptible populations for which special attention to transepidermal absorption of chemicals and medication may be warranted.
authors.affiliation: Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Ulla Nordström
authors.initials: UN
authors.lastname: Joensen
authors.forename: Niels
authors.initials: N
authors.lastname: Jørgensen
authors.forename: Michael
authors.initials: M
authors.lastname: Meldgaard
authors.forename: Hanne
authors.initials: H
authors.lastname: Frederiksen
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Andersson
authors.forename: Torkil
authors.initials: T
authors.lastname: Menné
authors.forename: Jeanne Duus
authors.initials: JD
authors.lastname: Johansen
authors.forename: Berit Christina
authors.initials: BC
authors.lastname: Carlsen
authors.forename: Steen
authors.initials: S
authors.lastname: Stender
authors.forename: Pal Bela
authors.initials: PB
authors.lastname: Szecsi
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Skakkebæk
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Thyssen
mesh_terms: D000293:Adolescent; D000328:Adult; D003430:Cross-Sectional Studies; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D010795:Phthalic Acids / Q000378:metabolism / Q000652:urine*; D013737:Testis / Q000502:physiology*; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010795:Phthalic Acids; C032279:phthalic acid