ENVIRONMENTAL CONTAMINANTS AND SPERM Y:X CHROMOSOME RATIO. Impact of androgen- and dioxin-related effects in vivo and in vitro

Abstract: During the last decades, there has been concern that the environmental contaminants, such as POPs, may contribute to sex ratio changes in offspring of exposed populations. Accidental exposure to TCDD has been shown to be associated with fewer sons in men who were exposed in adolescence or earlier in life. However, it is not known whether POPs could change the proportion of X- and Y-sperm. A variety of studies have indicated that POPs possess sex steroid-mimicking actions and/or AHR binding affinity. The aim of this thesis was to examine whether 1) the exposure to the POPs affects sperm Y:X ratio; 2) the endocrine disrupting action of POPs, in relation to observed changes in sperm sex chromosome ratio, may be modulated by genes involved in androgen and dioxin-mediated pathways; and 3) the functional interaction between AHR and the AR, which may play a part in regulation of sperm Y:X ratio, occurs in cultured Sertoli cells. The current study indicates that exposure to POPs may be involved in changing the proportion of Y-sperm. However, these findings were subject to modification, most likely due to varying exposure profiles and exposure levels, as indicated by diverging serum concentrations of CB-153 and p,p´-DDE in different cohorts (Sweden, Greenland, Warsaw and Kharkiv) studied. Moreover, our findings lend support to the notion that polymorphisms in genes involved in androgen and dioxin-related pathways may predispose to augmented effects of POPs in increasing the sperm Y:X ratio. Thus, p,p´-DDE levels were associated with Y-sperm proportion in Swedish fishermen carrying <22 CAG repeats in the AR and the AHRR P185A G-allele, but not in those missing one or both of these variants. We obtained, however, no evidence unambiguously demonstrating the mechanistic action of TCDD in interfering with androgen-dependent Pem reporter gene transcription in the SK11 Sertoli cells. A larger series of experiments or another study design may be required before any definitive conclusions can be drawn regarding the anti-androgenic capability of TCDD in testis. In conclusion, high exposure to POPs could affect sperm sex chromosome ratio. These findings were subject to inter-country differences, likely dependent on differing blood levels and composition of POPs. The AR/AHRR genotypes may act as effect modifiers predisposing to sperm sex ratio changes. The significance of androgen disrupting capability of AHR ligands in androgen-responsive cells of testis, however, waits for further studies.