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Objectives Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to investigate whether the CAG and GGN polymorphisms in the androgen receptor gene modify the effect of persistent organohalogen pollutant exposure on human sperm characteristics. Methods Semen and blood from 680 men [mean (SD) age 34 (10) years] from Greenland, Sweden, Warsaw (Poland) and Kharkiv (Ukraine) were collected. Persistent organohalogen pollutant exposure was assessed by measuring serum levels of 2,2,4,4,5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE). Semen characteristics (volume, sperm concentration, total count proportion of progressively motile and morphology) and DNA fragmentation index (DFI) were determined. CAG and GGN repeat lengths were determined by direct sequencing of leukocyte DNA. Results A statistically significant interaction was found between the CB-153 group and CAG repeat category in relation to sperm concentration and total sperm count (P=0.03 and 0.01, respectively). For p,p'-DDE, in the European cohorts a significant interaction was found in relation to DFI (P=0.01). For CAG

Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).

During recent years, it has been widely discussed whether environmental chemicals mimicking or inhibiting the action of endogenous hormones, the so-called endocrine disruptors (EDs), have an adverse effect on male reproductive function (Skakkebaek et al. 2001; Toppari et al. 1996). This debate followed reports indicating negative secular trends in sperm counts and concomitant increases in the incidence of testicular cancer as well as congenital abnormalities of male genitalia, such as cryptorchidism and hypospadias (Giwercman et al. 1993). These abnormalities, together with some forms of male infertility, constitute the so-called testicular dysgenesis syndrome (TDS). Furthermore, it has been suggested that TDS is due to a hormonal imbalance in the male reproductive system caused by fetal exposure to EDs (Skakkebaek et al. 2001). Compounds with potential ED effects, including persistent organohalogen pollutants (POPs), such as polychlorinated dibenzo-furans, polychlorinated dibenzo-p-dioxins, polychlorinated biphenyls (PCBs), dichloro-diphenyltrichloroethane (DDT), and dichloro-diphenyldichloroethene (p,p′-DDE; the most stable daughter compound of DDT), are ubiquitous environmental contaminants. These compounds are highly persistent, which results in bioaccumulation and biomagnification in the food chain. Measurable levels of PCBs and p,p′-DDE are found in a large proportion of the general population (Longnecker et al. 1997). Some of these chemicals can disrupt multiple endocrine pathways and induce a wide range of toxic responses (Toppari et al. 1996). A variety of studies have demonstrated their estrogenic, antiestrogenic, and androgen-interfering properties (Danzo 1997; Kelce et al. 1995). Furthermore, some of the PCBs have dioxin-like activity and therefore, through binding to the aryl hydrocarbon receptor (AhR) (Pocar et al. 2005), indirectly modify sex steroid action. Provided that POPs can act as EDs, one should expect these compounds to interfere with the normal hypothalamo–pituitary–gonadal axis. However, the data regarding such associations are relatively limited, and the overall picture of the effect of exposure on hormone levels is not uniform. It is not feasible to analyze all of the several hundred POP compounds that might be detected in human serum. Therefore, reliable proxy markers of exposure need to be used. The PCB congener 2,2′,4,4′5,5′-hexachloro-biphenyl (CB-153), found in relatively high concentrations in human serum, has been selected as a biomarker for POP exposure because of its very high correlation with the total PCB concentration (Glynn et al. 2000; Grimvall et al. 1997), the 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) equivalent (TEQ) from PCBs, and the total POP-derived TEQ (Gladen et al. 1999a) in Swedish and North American populations. Likewise, the major DDT metabolite p,p′-DDE, an anti-androgenic compound, is another good indicator of POP exposure. Previous studies from Greenland, Sweden, Poland, and Ukraine indicate that the exposure for p,p′-DDE is still considerable (Czaja et al. 1997; Deutch and Hansen 2000; Gladen et al. 1999b; Sjodin et al. 2002). As a part of a European Union–supported action, the impact of POP exposure on different aspects of male reproductive function was investigated in three European populations and among Greenland Inuit (Biopersistent Organochlorines in Diet and Human Fertility: Epidemiologic Studies of Time to Pregnancy and Semen Quality in Inuit and European Populations; INUENDO 2006). The aim of the present study was to assess the possible association between levels of CB-153 and p,p′-DDE in serum and reproductive hormones in males. Our hypothesis was that, provided that POPs act as EDs, the levels of the two exposure markers should to some degree correlate with concentrations of markers of testicular [testosterone, estradiol (E2), inhibin B] and/or pituitary [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] function. The action of POPs on the hypothalamo–pituitary–gonadal axis might be primarily exerted through the testis or via the hypothalamus/hypophysis. Because these chemicals can possess a multitude of endocrine effects, we did not, a priori, hypothesize which type of hormonal changes would be expected.

Recent studies have indicated that the proportion of male births has been declining in many countries during the past five decades (Allan et al. 1997; Marcus et al. 1998; Moller 1998; Parazzini et al. 1998; van der Pal-de Bruin et al. 1997). The cause of such a time-related trend is not known but has been suggested to result from an increasing exposure to endocrine disruptors such as persistent organohalogen pollutants (POPs) (Toppari et al. 1996). POPs—for example, polychlorinated dibenzofurans (PCDFs), polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated biphenyls (PCBs), dichlorodiphenyl-trichloroethane (DDT), and dichloro-diphenyldichloroethene (p,p′-DDE), the most stable metabolite of DDT—are ubiquitous environmental contaminants. Because of the hydrophobic and lipophilic nature and their long half-lives, these compounds are highly persistent and have a tendency to bio-accumulate and biomagnify in the food chain. Studies have shown that measurable levels of PCBs and p,p′-DDE are found in a large proportion of the general population [Arctic Monitoring and Assessment Programme (AMAP) 2003; Longnecker et al. 1997]. Some of these POPs can disrupt multiple endocrine pathways and induce a wide range of toxic responses (Toppari et al. 1996). A number of studies have demonstrated their estrogenic, antiestrogenic, dioxin-like, and androgen-competing properties (Andersen et al. 2002; Bonefeld-Jorgensen et al. 2001; Danzo 1997). Dioxin toxicity is most potent when animals are exposed in utero and lactationally. Although single exposure to dioxin has been investigated in a number of studies, there are few reports on repeated exposure of low dioxin doses, which more resembles the human situation. Recently, Ikeda et al. (2005) showed that in utero and lactational exposure of male rats to dioxin decreased the sex ratio of the subsequent generation. With respect to human exposure, two accidents that have attracted scientific and public attention are the Yucheng poisoning (Chen et al. 1985; Masuda et al. 1985) and the Seveso disaster (Mocarelli et al. 1996), both of which were associated with an increased proportion of girls born subsequent to paternal exposure to POPs (del Rio Gomez et al. 2002; Mocarelli et al. 1996, 2000). In human populations exposed to more moderate levels of POPs, both increased (Karmaus et al. 2002) and decreased (Rylander et al. 1995) male:female sex ratios have been reported. Therefore, the explanation of the secular trend in sex ratio is still lacking, and the mechanisms that can affect the proportion of males to females are not yet understood. Theoretically, offspring sex ratio may be related to events that occur before fertilization that favor selection of Y- or X-chromosome–bearing spermatozoa, events that occur after fertilization such as preferential development or survival of embryos of one sex, or a combination of both. Although recent human studies have indicated that paternal exposure to POPs has a deleterious effect on some semen characteristics (Guo et al. 2000; Hauser et al. 2003; Richthoff et al. 2003; Rignell-Hydbom et al. 2005), it is not yet known whether these compounds could change the proportion of X- and Y-bearing sperm. Recently, in a population composed of Swedish fishermen, we found a moderate positive association between serum levels of PCB-153 and of p,p′-DDE and the proportion of Y-bearing spermatozoa (Tiido et al. 2005). The study was part of a European Union–supported collaboration (INUENDO 2006) aiming to enlighten the impact of POP exposure on human reproductive function. Other populations included in this collaboration were recruited from Greenland, Poland (Warsaw), and Ukraine (Kharkiv). We have chosen to use the PCB congener, 2,2′,4,4′,5,5′-hexachloro-biphenyl (PCB-153) as a biomarker for POP exposure because of its very high correlations with the total PCB concentration (Glynn et al. 2000; Grimvall et al. 1997), the estimated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQ) from PCB, and the total POP-derived TEQ (Gladen et al. 1999), respectively. Likewise, the major DDT metabolite p,p′-DDE, an antiandrogenic compound, is another good indicator of the exposure. Previous studies from Greenland, Ukraine, and Sweden indicate that the exposure levels for p,p′-DDE are still considerable (Deutch et al. 2004; Gladen et al. 1999; Sjodin et al. 2000). The aim of the present study was to investigate whether the previously reported positive association between POP exposure markers and the proportion of Y-bearing sperm also occurs in three other populations characterized by different POP exposure profiles than the one found among Swedish fishermen (Jonsson et al. 2005). This information might indirectly add to our understanding of the biologic link between POP exposure and offspring sex ratio.

Summary Background In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816. Findings Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2–12·1] vs 6·5 months [4·7–8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56–1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding Pfizer Inc.

Persistent organochlorine pollutants (POPs) are suspected to interfere with hormone activity and the normal homeostasis of spermatogenesis. We investigated the relationships between sperm DNA fragmentation, apoptotic markers identified on ejaculated spermatozoa and POP levels in the blood of 652 adult males (200 Inuits from Greenland, 166 Swedish, 134 Polish and 152 Ukrainian). Serum levels of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (CB-153), as a proxy of the total POP burden, and of 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), as a proxy of the total DDT exposure were determined. Sperm DNA fragmentation was measured by using the TUNEL assay, whereas immunofluorescence methods were utilized for detecting pro-apoptotic (Fas) and anti-apoptotic (Bcl-xL) markers. Both TUNEL assay and apoptotic markers were statistically differed across the four populations. No correlation between neither sperm DNA fragmentation nor apoptotic sperm parameters and the large variations in POPs exposure was observed for the separate study groups. However, considering the European populations taken together, we showed that both %TUNEL positivity and Bcl-xL were related to CB-153 serum levels, whereas our study failed to demonstrate any relations between DDE and %TUNEL positivity and apoptotic sperm biomarkers (Fas and Bcl-xL) in any region or overall regions. These results suggest that CB-153 and related chemicals might alter sperm DNA integrity and Bcl-xL levels in European adult males, but not in the highly exposed Inuit men. Additional issues (genetic background, lifestyle habits and characterization of total xeno-hormonal activities) need to be investigated in order to fully assess the population variations observed.

Background Inconsistent results have been found in previous human studies on male reproductive toxicity of persistent organochlorine pollutants. The majority of studies have been conducted among selected populations of infertility clients or among occupational cohorts including a limited number of participants. Methods We conducted a cross-sectional study of semen quality and serum concentration of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) among 763 men. We included men from all regions in Greenland (n = 194), fishermen from Sweden (n = 185), inhabitants of the city of Kharkiv, Ukraine (n = 195), and inhabitants of the city of Warsaw, Poland (n = 189). Blood samples were analyzed for CB-153 and p,p'-DDE using gas chromatography-mass spectrometry and adjusted for serum lipids. Results Sperm concentration was not impaired with increasing serum CB-153 or p,p'-DDE levels in any of the separate groups or overall. Similarly, the proportion of morphologically normal sperm was not associated with either CB-153 or p,p'-DDE blood concentration. However, sperm motility was inversely related to CB-153 concentration in Greenland and the Swedish fishermen population. Across all 4 regions, the sperm motility decreased on average by 3.6% (95% confidence interval = 1.7% to 5.6%) per one-unit increase in the log of blood CB-153 (ng/g lipid). The concentration of p,p'-DDE was negatively associated with sperm motility in the Greenlandic population and in the compiled dataset. Conclusion Adult exposure to persistent organochlorine pollutants within the ranges observed in the present study is not likely to cause reduction in sperm concentration or morphology. However, higher exposure may be associated with impaired sperm motility.

BackgroundHuman 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).MethodsThe 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 17β-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.ResultsNo 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 andp,p'-DDE. For the Warsaw group a positive and negative correlation between XER andp,p'-DDE and estradiol equivalence level and CB-153 levels was found.ConclusionNo 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.