Environmental Exposures and Sex Chromosome Abnormalities in Human Sperm Open Access
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Despite evidence that US infertility is increasing and environmental exposures may be impacting human reproduction, the reproductive effects of environmental chemicals remain understudied, particularly in men. Some genetic defects and disorders are transmitted by spermatozoa and several chromosomal abnormalities come from the father. In germ cells, failure of sex chromosomes (X or Y) to separate properly during meiosis (I or II) results in an extra or missing chromosome, known as aneuploidy and these errors in chromosome number are the most common chromosomal abnormality in humans. Disomy, or an extra X or Y chromosome, is the most frequent form of aneuploidy observed in human sperm. Limited information has been published about exposures to endocrine-disrupting chemicals (EDCs), such as organophosphate (OP) and pyrethroid (PYR) pesticides, and their association with altered frequency of sperm chromosomal abnormalities. Although extensive literature on pesticide toxicology is available, many hormone-mediated effects, specifically on the testes, are not well understood. This dissertation involved three separate investigations. Study subjects were men from a parent study assessing the impact of environmental exposures on male reproductive health at the Massachusetts General Hospital (MGH) Fertility Center (2000-2003). Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total sex chromosome disomy in sperm nuclei. Urine was analyzed for common PYR and OP metabolites. Poisson regression models were used to calculate incidence rate ratios (IRRs) for each disomy type by the exposure of interest, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. Sensitivity analyses were also conducted. Interactions between PYR and OP metabolites and associations with each disomy outcome were examined in the adjusted models. First, we investigated environmental exposure to PYRs and their association with sperm disomy among adult men (n=181). Inverse associations were observed between PYR exposure levels and most disomy outcomes. Second, a similar investigation was conducted with OP pesticides (n=159). Increased and inverse IRRs were associated with specific OP metabolites. Total sum of OP metabolites concealed individual associations for specific OP metabolites. Dose-response relationships between OP exposure levels and disomy appeared nonmonotonic, with an increase in disomy rates between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. Finally, we examined the hypothesis that pesticide mixtures (OP/PYR) and their potential interactions alter associations with sperm disomy (n=159). Significant interactions were identified between OP/PYR mixtures and sperm disomy. Increased IRRs, higher than the rates previously detected for each individual chemical class, were observed when evaluating the associations between disomy outcomes and pesticide mixtures. Nonmonotonic relationships between pesticide mixtures and disomy demonstrated that further modeling work is needed to: a) determine the optimal method to evaluate pesticide mixtures with different modes of action; b) investigate interactions using non-logistic models; and c) identify the mechanisms by which EDCs affect health reproductive outcomes. Our findings showed that PYR and OP pesticides altered the associations of sperm disomy, suggesting that the impacts of EDCs on testis function need further characterization in epidemiologic studies.