Sperm Y:X chromosome ratio and androgen response in men exposed to environmental pollutants

Abstract: The last several decades have seen an increase in male infertility concomitant with a decline in the birth sex ratio. The conditions are believed to be linked to increased exposure to endocrine disrupting chemicals (EDCs), including the persistent organic pollutants or lifestyle factors e.g. smoking. The mechanism behind the lowered birth sex ratio is unknown, but might be due to an EDC-induced skewing of the proportions of Y to X chromosome bearing sperms. The aims of this thesis were: to elucidate possible associations between the sperm Y:X ratio and EDCs in several highly exposed populations, to evaluate any relationships that might exist between the Y:X ratio and sperm parameters in subfertile men, and to investigate the effect of smoking on androgen regulation in vivo as well as in vitro. The sperm sex chromosome ratio was investigated by fluorescent in situ hybridization (FISH) in n=449 men from the Faroe Islands and compared to n=414 men from Greenland, Ukraine and Poland. Infertile men n=190 were enrolled at a fertility clinic in Denmark and androgenicity in smoking men was measured in n=2156 men recruited for several previous epidemiological studies. The effect of smoking was assessed in a reporter system with the prostate specific antigen promoter driving a luciferase gene, in the presence or absence of various concentrations of the cigarette smoke constituent Benzo[?]Pyrene (BaP). In men from the Faroe Islands, the Y:X ratio was lower than in other highly exposed populations and a negative association between the sperm sex chromosome ratio and both dichlorodiphenyl dichloroethane (DDE) and selected polychlorinated biphenyls (PCBs) in the somewhat older, proven fertile men was found. A positive trend between the Y:X ratio and perfuorooctane sulfonate (PFOS) in a combined population of men from Greenland, Ukraine and Poland was found. The opposite association was observed in the Greenland Inuit alone. In subfertile men, a positive association between the Y:X ratio and progressive motility was noted. In two cohorts of smoking men, positive trends between groups of men with increasing exposure to cigarette smoke and androgen insensitivity was found. The in vitro experiments showed a significant deactivation of the AR at the highest BaP concentration. To conclude, high concentrations of EDCs influence the Y:X ratio in highly exposed populations i.e. men from Greenland and the Faroe Islands. The inter-population differences in Y:X ratio might be genetic or due to lifestyle factors such as diet. Men with low progressive motility had lower Y:X ratio, possibly explaining the low birth sex ratio seen following intra cytoplasmic sperm injection. Indications that smoking has adverse effects on the androgenicity were observed both in vivo and in vitro.