Xenohormone transactivities are inversely associated to serum POPs in Inuit.

BACKGROUND: The persistent organic pollutants (POPs) are highly lipophilic and resistant to biodegradation and found in e.g. seafood and marine mammals. Greenlandic Inuit have high intake of marine food and thus high POP burden that varies according to local conditions and dietary preference. We do for the very first time report the serum POP related non-steroidal xenohormone activity of Inuit across Greenland. The aims were 1) to determine the integrated xenohormone bioactivities as an exposure biomarker of the actual lipophilic serum POP mixture measuring the effect on estrogen (ER) and androgen receptor (AR) transactivity in citizens from different Greenlandic districts and 2) to evaluate associations to serum POP markers (14 PCBs and 10 pesticides) and lifestyle characteristics. METHODS: Serum samples from 121 men and 119 women from Nuuk, Sisimiut and Qaanaaq were extracted using SPE-HPLC fractionation to obtain the serum POP fraction free of endogenous hormones. The serum POP fraction was used for determination of xenohormone transactivity using ER and AR reporter gene assays. RESULTS: In overall, the xenohormone transactivities differed between districts as well as between the genders. Associations between the transactivities and age, n-3/n-6 and smoker years were observed. The xenoestrogenic and xenoandrogenic transactivities correlated negatively to the POPs for the combined female and male data, respectively. CONCLUSION: The non-steroidal xenohormone transactivities can be used as an integrated biomarker of POP exposure and lifestyle characteristics. The actual serum POP mixtures antagonized the age adjusted sex hormone receptor functions. Comparison of different study populations requires in addition to age inclusion of diet and lifestyle factors.

Xenobiotic activity in serum and sperm chromatin integrity in European and inuit populations.

Lipophilic persistent organic pollutants (POPs) are ubiquitous in the environment and suspected to interfere with hormone activities and reproduction. In previous studies we demonstrated that POP exposure can affect sperm DNA integrity and differences between Inuits and Europeans in sperm DNA integrity and xenobiotic activity were observed. The aim of this study was to investigate possible relations between human sperm chromatin integrity and the xenobiotic serum activity of lipophilic POPs assessed as effects on the estrogen (ER), androgen (AR), and/or aryl hydrocarbon (AhR) receptors. Human sperm chromatin integrity was assessed as DNA fragmentation index (%DFI) and high DNA stainability (%HDS) using the flow cytometric sperm chromatin structure assay (SCSA). Xenobiotic receptor activities were determined using chemically activated luciferase gene expression (CALUX) assay. The study included 53 Greenlandic Inuits and 247 Europeans (Sweden, Warsaw (Poland) and Kharkiv (Ukraine)). A heterogeneous pattern of correlations was found. For Inuits, ER and AhR activities and %DFI were inversely correlated, whereas a positive correlation between AR activity and %DFI was found for Europeans. In contrast, no correlation between receptor activities and %HDS was observed for Inuits but for Europeans positive and negative correlations were observed between ER and AR activities and %HDS, respectively. We suggest that the different patterns of xenobiotic serum activities, in combination with diet associated factors and/or genetics, might be connected to the observed differences in sperm chromatin integrity between the Inuits and Europeans.

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations.

Persistent organic pollutants (POPs) can interfere with hormone activities and are suspected as endocrine disrupters involved in disorders, e.g. reproductive disorders. We investigated the possible relation between the actual integrated serum xenoestrogenic, xenoandrogenic and aryl hydrocarbon receptor (AhR) activities, and the sperm DNA damage and sperm apoptotic markers of 262 adult males (54 Inuits from Greenland, 69 from Warsaw (Poland), 81 from Sweden, and 58 from Kharkiv (Ukraine)) exposed to different levels of POPs. Xenobiotic-induced receptor activities were determined by receptor-mediated luciferase reporter gene expression. Sperm DNA damage was measured using terminal deoxynucleotidyl transferase-driven dUTP nick labeling assay (TUNEL) and pro- (Fas) and anti-apoptotic (Bcl-xL) markers were determined by immune methods. Different features of xenobiotic-induced receptor activity in serum and sperm DNA fragmentation and apoptotic markers existed between the Inuits and the European Caucasians. Negative correlations between xenobiotic-induced receptor activities and DNA damage were found for Inuits having relatively lower xenoestrogenic, lower dioxin-like activity, and lower sperm DNA damage, but higher xenoandrogenic activity. In contrast, in the European groups, xenobiotic-induced receptor activities were found to be positively correlated with the DNA damage. Further research must elucidate whether altered receptor activities in concerted action with genetic and/or nutrient factors may have protecting effect on sperm DNA damage of the Inuit population.

Semen quality in relation to xenohormone and dioxin-like serum activity among Inuits and three European populations.

BACKGROUND: Semen quality in humans may be influenced by exposure to endocrine-disrupting compounds. OBJECTIVES: We analyzed associations between semen characteristics and serum xenoestrogen receptor (XER), xenoandrogen receptor (XAR), and aryl hydrocarbon receptor (AhR) transactivity. XER and XAR activity were measured in serum samples cleared for endogenous steroid hormones and AhR activity in raw lipophilic serum extracts free of proteins. RESULTS: All together, 319 men from Warsaw (Poland), Greenland, Kharkiv (Ukraine), and Sweden provided semen and blood samples. No strong and consistent associations between xenobiotic activity and semen quality measures were observed in the four populations. However, when the data were combined across populations sperm concentration increased 40% per unit increase in XER activity [95% confidence interval (CI), 1-79%] in the subgroup with XER activity below the reference level. Among subjects with XER activity above the reference level an increase of 14% (95% CI, 2-28%) was found. Furthermore, an increase of 10% motile sperm per unit increase in XER activity below reference level (95% CI, 0.2-20) was found. We are unable to exclude that the associations are chance findings. CONCLUSION: Alteration of XER, XAR, or AhR transactivity within the range found in serum from the general European and Inuit population seems not to markedly deteriorate sperm cell concentration, motility, or morphology in adult men.

Xenoandrogenic activity in serum differs across European and Inuit populations.

BACKGROUND: Animal and in vitro studies have indicated that human male reproductive disorders can arise as a result of disrupted androgen receptor (AR) signalling by persistent organic pollutants (POPs). Our aim in the present study was to compare serum xenoandrogenic activity between study groups with different POP exposures and to evaluate correlations to the POP proxy markers 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE). METHODS: We determined xenoandrogenic activity in the serum fraction containing the lipophilic POPs but free of endogenous hormones. Adult male serum (n = 261) from Greenland, Sweden, Warsaw (Poland), and Kharkiv (Ukraine) was analyzed. Xenoandrogenic activity was determined as the effect of serum extract alone (XAR) and in the presence of the synthetic AR agonist R1881 (XARcomp) on AR transactivated luciferase activity. RESULTS: The study groups differed significantly with respect to XARcomp activity, which was increased in the Inuits and decreased in the European study groups; we observed no difference for XAR activity. We found the highest level of the AR antagonist p,p'-DDE in Kharkiv, and accordingly, this study group showed the highest percent of serum samples with decreased XARcomp activities. Furthermore, the percentage of serum samples with decreased XARcomp activities followed the p,p'-DDE serum level for the European study groups. No correlations between serum XAR or XARcomp activities and the two POP markers were revealed. CONCLUSIONS: The differences in XARcomp serum activity between the study groups suggest differences in chemical exposure profiles, genetics, and/or lifestyle factors.

Xenoestrogenic activity in blood of European and Inuit populations.

BACKGROUND: Human exposure to persistent organic pollutants (POPs) is ubiquitous and found in all individuals. Studies have documented endocrine disrupting effects and impact on reproduction. The aim of the present study was to compare the level of xenoestrogenic activity in serum of groups with varying POP exposure, and to evaluate correlations to the POP biomarkers, 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE). METHODS: The study included 358 men: Greenlandic Inuit's, Swedish fishermen, and Warsaw (Poland) and Kharkiv (Ukraine) inhabitants. Xenoestrogenicity of serum extracts alone (XER) and XER competitive (XERcomp) effect on 17beta-estradiol induced estrogen receptor (ER) transactivity were assessed in the hormone free, lipophilic serum fraction containing the POPs using the MVLN human breast cancer cell line. RESULTS: No agonistic XER activity was exhibited for Inuit serum samples, while 12 - 24% of the European samples had detectable agonistic XER activity. On the contrary, 71% of Inuit serum samples antagonized XERcomp compared to 7 - 30 % in the other regions. XER and XERcomp were not or weakly correlated to the two POP markers. XER activity of Inuit samples was negatively associated to levels of CB-153 and p,p'-DDE. For the Warsaw group a positive and negative correlation between XER and p,p'-DDE and estradiol equivalence level and CB-153 levels was found. CONCLUSION: No strong consistent association between xenoestrogenic net activity and the two POP markers was found. The results showed that the selected POP markers alone can not predict the integrated xenoestrogenic serum activity. Correlations to the POP markers were found at the extreme edge; the Inuit's and Warsaw study groups eliciting high frequency of samples with ER antagonistic and agonistic activity, respectively. We suggest that the variation in xenoestrogenic serum activity reflects differences in POP exposure mixture, genetic factors and/or life style factors.