Ina Olmer Specht

Associations between serum phthalates and biomarkers of reproductive function in 589 adult men.

Phthalates which are widely used, are ubiquitous in the environment and in some human tissues. It is generally accepted that phthalates exert their toxic action by inhibiting Leydig cell synthesis of testosterone, but in vitro studies have also shown anti-androgenic effects at the receptor level. Some cross-sectional studies have shown inverse associations between urinary levels of phthalates and reproductive hormones, but results are conflicting and the evidence base is limited. The aim of this study was to investigate if levels of di-2-ethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) metabolites in serum are associated with serum concentrations of male reproductive hormones and semen quality. A secondary aim was to investigate metabolic pathways of DEHP and DiNP on semen quality and reproductive hormones. A cross-sectional sample of 589 spouses of pregnant women from Greenland, Poland and Ukraine were enrolled between 2002 and 2004. The men gave semen and blood samples and were interviewed. Six phthalate metabolites of DEHP and DiNP were measured by liquid chromatography tandem mass spectrometry in serum. The metabolites were summed according to their molar weight. We observed significant inverse associations between serum levels of the metabolites, the proxies and serum testosterone. Negative associations were also discovered between some metabolites and sex hormone-binding globulin, semen volume and total sperm count. Findings are compatible with a weak anti-androgenic action of DEHP metabolites, but less so for DiNP metabolites. Metabolic pathways differed significantly between the three study sites, but without major effect on semen quality or reproductive hormones.

Sperm DNA integrity in relation to exposure to environmental perfluoroalkyl substances - a study of spouses of pregnant women in three geographical regions.

Perfluoroalkyl substances (PFASs) can interfere with male reproductive function, but evidence in humans is limited. Six hundred four fertile men (199 from Greenland, 197 from Poland and 208 from Ukraine) were enrolled in the study. We measured four PFASs in serum (PFOS, PFOA, PFNA and PFHxS) and concurrent DNA damage in spermatozoa by sperm chromatin structure assay (SCSA) and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, apoptotic markers in semen (Fas-receptor and Bcl-xL), and reproductive hormones in serum. No association between PFASs and SCSA, apoptotic markers or reproductive hormones emerged. We observed a slight increase in SHBG and TUNEL-positivity with increased PFOA exposure in men from Greenland. Thus, consistent evidence that PFAS exposure interferes with sperm DNA fragmentation, apoptosis or reproductive hormones was not found.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis

BACKGROUND More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commissions list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91–1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p′-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04–1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure–response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure–outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml(-1) in Greenland (0.2-385.8 ng ml(-1)), 1.0 ng ml(-1) in Poland (0.2-6.4 ng ml(-1)) and 1.0 ng ml(-1) in Ukraine (0.2-4.9 ng ml(-1)). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (β=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (β=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH × testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml(-1) has adverse effects on biomarkers of male reproductive health.

Serum Phthalate Levels and Time to Pregnancy in Couples from Greenland, Poland and Ukraine

Phthalates are ubiquitous industrial chemicals that have been associated with altered reproductive function in rodents. Several human studies have reported an inverse association between male testosterone and phthalate levels. Our aim was to investigate time to pregnancy (TTP) according to serum levels of diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) metabolites in both partners. In 2002-2004 we enrolled 938 pregnant women and 401 male spouses from Greenland, Poland and Ukraine. Six oxidized metabolites of DEHP and DiNP were summarized for each of the two parent compounds to provide proxies of the internal exposure. We used Cox discrete-time models to estimate fecundability ratios (FR) and 95% confidence intervals (95% CIs) for men and women according to their proxy-DEHP or -DiNP serum levels adjusted for a fixed set of covariates. The FR was slightly elevated among women with high levels of DEHP (FR=1.14, 95% CI 1.00;1.30) suggesting a shorter TTP in these women. The FR was unrelated to DiNP in women, whereas the results for men were inconsistent pointing in opposite directions. First-time pregnant women from Greenland with high serum DiNP levels had a longer TTP. This study spanning large contrast in environmental exposure does not indicate adverse effects of phthalates on couple fecundity. The shorter TTP in women with high levels of DEHP metabolites is unexplained and needs further investigation.

Exposure to Perfluoroalkyl Substances and Sperm DNA Global Methylation in Arctic and European Populations

Perfluoroalkyl substances (PFASs) are widely used in a variety of industrial processes and products, and have been detected globally in humans and wildlife. PFASs are suspected to interfere with endocrine signaling and to adversely affect human reproductive health. The aim of the present study was to investigate the associations between exposure to PFASs and sperm global methylation levels in a population of non‐occupationally exposed fertile men. Measurements of PFASs in serum from 262 partners of pregnant women from Greenland, Poland and Ukraine, were also carried out by liquid chromatography tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) were detected in 97% of the blood samples. Two surrogate markers were used to assess DNA global methylation levels in semen samples from the same men: (a) average DNA methylation level in repetitive DNA sequences (Alu, LINE‐1, Satα) quantified by PCR‐pyrosequencing after bisulfite conversion; (b) flow cytometric immunodetection of 5‐methyl‐cytosines. After multivariate linear regression analysis, no major consistent associations between PFASs exposure and sperm DNA global methylation endpoints could be detected. However, since weak but statistically significant associations of different PFASs with DNA hypo‐ and hyper‐methylation were found in some of the studied populations, effects of PFASs on sperm epigenetic processes cannot be completely excluded, and this issue warrants further investigation. Environ. Mol. Mutagen. 55:591–600, 2014.

Health Effects of PCBs in Residences and Schools (HESPERUS): PCB – health Cohort Profile

Polychlorinated-biphenyls (PCBs) were introduced in the late 1920s and used until the 1970s when they were banned in most countries due to evidence of environmental build-up and possible adverse health effects. However they still persist in the environment, indoors and in humans. Indoor air in contaminated buildings may confer airborne exposure markedly above background regional PCB levels. To date, no epidemiological studies have assessed the health effects from exposure to semi-volatile PCBs in the indoor environment. Indoor air PCBs are generally less chlorinated than PCBs that are absorbed via the diet, or via past occupational exposure; therefore their health effects require separate risk assessment. Two separate cohorts of individuals who have either attended schools (n = 66,769; 26% exposed) or lived in apartment buildings (n = 37,185; 19% exposed), where indoor air PCB concentrations have been measured were created. An individual estimate of long-term airborne PCB exposure was assigned based on measurements. The cohorts will be linked to eight different national data sources on mortality, school records, residential history, socioeconomic status, and chronic disease and reproductive outcomes. The linking of indoor air exposures with health outcomes provides a dataset unprecedented worldwide. We describe a project, called HESPERUS (Health Effects of PCBs in Residences and Schools), which will be the first study of the long term health effects of the lower-chlorinated, semi-volatile PCBs in the indoor environment.

Environmental Hexachlorobenzene exposure and human male reproductive function.

Hexachlorobenzene (HCB) is a persistent environmental fungicide that may disrupt androgen regulation. The aim of this study was to investigate associations between HCB levels and biomarkers of male reproductive function. 589 Spouses of pregnant women from Greenland, Poland and Ukraine were enrolled between 2002 and 2004. The men provided semen and blood samples and were interviewed. HCB was measured in serum by gas chromatography. The mean serum concentrations of HCB were higher in Ukraine (182.3ng/g lipid) and Greenland (79.0ng/g lipid) compared to Poland (14.2ng/g lipid). Sex hormone binding globulin (SHBG) and free androgen index (FAI) were associated with HCB in men from Ukraine and Poland. This study spanning large differences in environmental HCB exposure levels shows a positive association for SHBG and negative association for FAI with high serum levels of HCB in fertile men, but without major consequences for semen quality and the Inuit study population.

Cadmium may impair prostate function as measured by prostate specific antigen in semen: A cross-sectional study among European and Inuit men

We investigated the association between cadmium in blood and the concentration of the prostate specific antigen (PSA) in semen, including the modifying effects of zinc or the CAG polymorphism in the androgen receptor (AR). Blood and semen samples were collected from 504 partners of pregnant women in Greenland, Poland and Ukraine. We found an inverse trend between cadmium and PSA (log(β) = -0.121, 95% confidence interval (CI): -0.213; -0.029, P = 0.0103) in Greenlandic men. Similar results were observed in men with a high number of CAG repeats (CAG 24) (log(β) = -0.231, 95% CI: -0.363; -0.098, P = 0.0009). Inverse trends between cadmium and PSA were found when semen zinc concentrations were below the median value for men from Ukraine and Greenland. These outcomes suggest that cadmium may impair prostate function, as measured by PSA in semen, while high zinc levels and a low number of CAG repeats protects against this action.

Environmental cadmium and lead exposure and anti-Müllerian hormone in pregnant women

BACKGROUND Anti-Müllerian Hormone (AMH) has been suggested as a marker for ovarian function. Cadmium and lead have been suggested to reduce female fecundity. In this study we aimed to investigate whether environmental exposure to cadmium and lead was associated with alterations in serum-AMH. MATERIALS AND METHOD The associations between serum-AMH and whole blood cadmium or lead were investigated by general linear models in a population-based sample of 117 pregnant women. RESULTS The mean concentrations of blood cadmium and lead were 0.71μg/L and 17.4μg/L, respectively. The mean serum-AMH was 17.3pmol/L. No association between lead and AMH was detected. In the cadmium analysis the adjusted mean AMH level (95% CI) in the highest exposure tertile was 12.4 (6.4;23.8) compared to 5.6 (2.7;11.4) in the lowest exposure tertile (p=0.06). CONCLUSION The study provides suggestive evidence that environmental exposure to cadmium, but not lead, may alter the level of AMH.