Effects of Environmental Phthalates and Chemical Mixtures on Male Puberty and Semen Quality

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ABSTRACT The pubertal transition from pre-puberty to sexual maturity entails dynamic physical, behavioral, and hormonal changes. Although studies report temporal trends towards an earlier onset of puberty in girls, there are limited data in boys on temporal trends of pubertal onset. Moreover, there is a dearth of longitudinal studies on the impact of environmental chemicals on male puberty. Phthalates are one class of chemicals for which there is scientific and regulatory concern regarding their potential effects on male pubertal development and testicular function. This concern is based upon numerous experimental studies in rodents showing that some phthalates are anti-androgenic and are male developmental and reproductive toxicants, causing delayed pubertal onset, decreased serum testosterone concentrations and impaired semen quality. Based on the experimental data and the documented widespread human exposure to phthalates, in this competing renewal we propose to investigate the effect of phthalates (individual phthalates and their mixtures) on male pubertal development, reproductive hormones and semen quality. We will leverage our unique well-defined longitudinal cohort study of 499 Russian boys followed from enrollment at age 8 until 21 years. Our pilot data on a small subset of the cohort shows high urinary concentrations of multiple anti-androgenic phthalate metabolites. In the competing renewal, we will measure urinary concentrations of phthalate metabolites in archived urine samples collected annually during twelve years of follow-up. To evaluate the effect of phthalate exposure during three sensitive windows, we will pool annual urine samples for each boy as follows: 1) pre-pubertal window (pool all samples collected at annual visits when testicular volume <4 ml), 2) early through mid-pubertal window (pool all samples collected at annual visits when testicular volume is between 4 and less than 15 ml), and 3) late-pubertal window (pool all samples collected at annual visits when testicular volume is 15 ml or greater). Our study will be one of the first prospective cohort studies in boys that will assess the effect of phthalate exposure at three sensitive windows on puberty and semen quality. We also have the unique opportunity to investigate the effect of exposure to real-life mixtures of phthalates and environmental chemicals/metals (organochlorines, including dioxins, furans, PCBs, pesticides and lead were measured in our current funding period) on puberty and semen quality. Altered timing and progression of puberty are an important public health issue because they may have adverse effects on growth, social functioning, cognitive and behavioral development, and adult metabolic and reproductive health. Furthermore, poor semen quality increases risk of infertility. In conclusion, elucidating the association of prevalent environmental chemicals with adverse male reproductive development may reveal potentially modifiable risk factors (for example, reducing phthalate use in consumer products).