Endocrine Disrupting Chemicals and Male Reproductive Health

Abstract

Phthalates and parabens are endocrine disrupting chemicals with ubiquitous human exposure. Medication coatings and personal care products (PCPs) are important exposure sources, however, their contribution to men’s exposure as well as health effects are understudied. Dibutyl phthalate (DBP) is used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease. This work presents novel innovative methods to assess whether high-DBP exposure from mesalamine (>1000x background-exposure) altered serum reproductive hormones and semen quality. We took advantage of different mesalamine formulations with/without DBP to conduct a prospective crossover-crossback study (MARS study). We estimated crossover, crossback and carryover effects using multivariable linear mixed effect models. We conclude that high-DBP exposure disrupted serum levels of pituitary-gonadal hormone levels that largely reversed after exposure removal, but only in men with no/short history (< 3 years) of previous high-DBP exposure. However, high-DBP exposure among men with no history of high-DBP mesalamine use led to a reduction, primarily in sperm motility that was not reversed but became more pronounced (carried-over) after removal of exposure for four months. Paradoxically, among men with longer duration of high-DBP exposure, removal of the exposure did not change hormone levels or semen quality, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and spermatogenesis making them insensitive to DBP-exposure changes. Based on this work, we offer recommendations for designing future crossover-crossback studies including longer crossover-crossback durations and different timing of sample collection. In the prospective EARTH cohort study, we assessed PCPs’ contribution to men’s phthalate and paraben exposure. We estimated the changes in urinary concentrations associated with PCP-use using multivariable linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP-use. We identified ten PCPs of relevance and demonstrated that their use within six hours of urine collection strongly predicted specific phthalate and paraben urinary concentrations. We also offer concise PCP-use information by only asking specific questions about the use of the most relevant PCPs to help future research in decreasing missingness, improving recall, and decreasing misclassification while optimizing research cost and time.