Academic journal article Environmental Health Perspectives

Associations of Filaggrin Gene Loss-of-Function Variants with Urinary Phthalate Metabolites and Testicular Function in Young Danish Men

Academic journal article Environmental Health Perspectives

Associations of Filaggrin Gene Loss-of-Function Variants with Urinary Phthalate Metabolites and Testicular Function in Young Danish Men

Article excerpt

Introduction

In human stratum corneum of the skin, protein-enriched corneocytes are embedded in a lipid-rich matrix that impedes egress of water and penetration of pathogenic microorganisms, allergens, and noxious chemicals. To maintain skin hydration, abundant intracellular filaggrin proteins are hydrolyzed into amino acids and their deiminated products, collectively referred to as the "natural moisturizing factors" (Gruber et al. 2011). Filaggrin deficiency due to the presence of one or more loss-of-function variants in the filaggrin gene (FLG) is observed in approximately 10% of lightly pigmented Europeans and in a slightly lower proportion of Asians (Irvine et al. 2011). These variants cause ichthyosis vulgaris (Smith et al. 2006), which is characterized by xerosis, scaling, and keratosis pilaris as well as palmar and plantar hyperlinearity. Permeation of allergens seems to be increased in filaggrin-depleted skin (Fallon et al. 2009; Gruber et al. 2011; Scharschmidt et al. 2009), and an increased risk of atopic dermatitis, asthma, rhinitis, food allergies, and nickel sensitization have been observed (Brown et al. 2011; Palmer et al. 2006; Thyssen et al. 2010). Clinical trials are currently being conducted to study whether primary prevention of atopic disorders is possible using topical therapy with moisturizers (Irvine et al. 2011).

Diesters of 1,2-benzenedicarboxylic acid, commonly referred to as phthalates, are man-made chemicals used in a wide range of consumer products, including moisturizers and other cosmetics. Although phthalates are rapidly metabolized and excreted in the urine following absorption, humans are continuously exposed by skin contact with, for example, cosmetics, fragrances, solvents, and plastics (Wittassek et al. 2011), as well as through the diet and via inhalation. An inverse association between phthalate exposure and markers of testicular function has been reported in some human studies (Meeker et al. 2009; Mendiola et al. 2011). Animal studies have established that certain phthalates act as endocrine disruptors, resulting in developmental abnormalities of the male reproductive tract as well as inhibition of testicular testosterone production in prenatally or perinatally exposed animals (Boberg et al. 2011; Gray et al. 2000). Although the pathogenic effects of phthalate exposure on testicular function in humans is not yet clear, certain phthalates inhibit testosterone synthesis in cultured adult human testes at concentrations estimated to be within the range observed in epidemiological studies (Desdoits-Lethimonier et al. 2012).

In the present study, we addressed the question of whether male FLG-null carriers would have increased internal exposure to phthalate metabolites, and if so, whether this would affect testicular function.

Methods

Study population. All Danish men are called to a compulsory examination the year of their 18th birthday to determine fitness for military service. On the day they went for this examination, men residing in the Copenhagen, Denmark, area were asked to participate in a study on semen quality. A total of 881 men volunteered during 2007-2009 for a study on urinary phthalate excretion and testicular function (Joensen et al. 2012). The participation rate was approximately 30%, which is higher than in other population-based semen-quality studies (Jorgensen et al. 2002). Basic study details have been described previously (Jorgensen et al. 2012). Each man underwent a physical examination focusing on reproductive development, completed a questionnaire, and gave samples of spot urine, semen, and blood, in most cases all within 1 hr. Ejaculation abstinence period and time of blood sampling were recorded. All urine, semen, and blood samples were collected between 0840 hours and 1230 hours (median time, 1000 hours). In 2011, FLG genotyping was performed according to a protocol developed for the present study. DNA samples from 13 of the 881 men were missing or of poor quality; for another 7 men, the urine sample was too small to analyze osmolality. …

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