Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.
We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.
Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.
Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.
To investigate the association between serum antim?llerian hormone (AMH) and other reproductive parameters in young women.
Population-based cohort of 256 women: 180 were users and 76 were nonusers of hormonal contraceptives.
Antral follicles, androgens, age at menarche, and duration and regularity of menstrual cycle.
AMH levels were lower among users of hormonal contraceptives compared to nonusers. Among nonusers, women with AMH levels in the upper tertile had 55% (95% confidence interval [CI]: 22%-99%) higher levels of total T and 8% (95% CI = 2%-15%) longer menstrual cycles than women with AMH levels in the lower tertile. An increase of 1 ng/mL in AMH was associated with 45% (95% CI = 6%-97%) higher prevalence of irregular menstrual cycles. These associations were not seen among users of hormonal contraceptives. A strong relationship between AMH and follicle number was found in both users and nonusers.
AMH measurements were found to be applicable in evaluation of the reproductive function of young women. However, there may be differences in the way that serum AMH levels can be interpreted depending on whether the woman uses hormonal contraceptives or not.
Animal studies indicate that some phthalate metabolites may harm female reproductive function.
We assessed the associations between exposure to phthalate metabolites and pregnancy loss.
Using a previously established cohort of couples planning their first pregnancy, we analyzed four primary and two oxidized secondary phthalate metabolites in urine samples collected on day 10 after the first day of the last menstrual period before conception occurred (n = 128) and during the previous cycle (if any, n = 111). Subclinical embryonal loss was identified by repeated measurement of urinary human chorionic gonadotropin, and information on clinical spontaneous abortions was obtained by telephone interview with the mother.
Pregnancy loss (n = 48) was increased among women with urinary concentration of monoethylhexyl phthalate (MEHP) in the upper tertile in the conception sample compared with women in the lowest tertile [adjusted odds ratio (OR) = 2.9; 95% confidence interval (CI): 1.1, 7.6]. The corresponding OR for subclinical embryonal loss (n = 32) was 40.7 (95% CI: 4.5, 369.5).
The phthalate metabolite MEHP was associated with higher occurrence of pregnancy loss. Because this is the first human study to show this association and the sample size is small, the findings need to be corroborated in independent studies.
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Association of maternal serum concentrations of 2,2', 4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) levels with birth weight, gestational age and preterm births in Inuit and European populations.
Epidemiological studies on the association between maternal exposure to persistent organic pollutants (POPs) and fetal growth alteration report inconsistent findings which weights in favor of additional studies.
Blood samples were collected from interviewed pregnant women in Greenland (572), Kharkiv (611) and Warsaw (258) and were analyzed for CB-153 and p,p'-DDE by gas chromatography-mass spectrometry. Data on birth weight, gestational age and preterm birth were obtained for 1322 singleton live births. We examined the association between natural log-transformed serum POPs concentration and birth weight and gestational age using multiple linear regression and the association with prematurity using logistic regression controlling for potential confounding factors.
The median serum concentrations of CB-153 and p,p'-DDE were for Inuit mothers 105.6 and 298.9, for Kharkiv mothers 27.0 and 645.4 and for Warsaw mothers 10.7 and 365.2 ng/g lipids, respectively. Increase in CB-153 concentration by one unit on the log scale in Inuit mothers serum was associated with significant decrease in infant birth weight of -59 g and gestational age by -0.2 week. Decreases observed in the cohorts in Kharkiv (-10 g and -0.1 week) and in Warsaw (-49 g and -0.2 week) were not statistically significant. Increase in p,p'-DDE concentration by one unit on the log scale was associated with a statistically significant decrease in infant birth weight of -39.4 g and -104.3 g and shortening of gestational age of -0.2 week and -0.6 week in the Inuit and Warsaw cohorts, respectively. In the Kharkiv cohort decrease in birth weight (-30.5 g) was not significant, however a shortening of gestational age of -0.2 week per increase in p,p'-DDE concentration by one unit on the log scale was of the borderline significance. There was no significant association between CB-153 and p,p'-DDE concentrations and risk of preterm birth however, in all cohorts the odds ratio was above 1.
In utero exposure to POPs may reduce birth weight and gestational age of newborns however, new insights as to why results vary across studies were not apparent.
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Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine-disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern.
We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels.
We recruited 169 male offspring (19-21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988-1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30.
Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (ptrend = 0.01) and total sperm count (ptrend = 0.001) and with higher adjusted levels of luteinizing hormone (ptrend = 0.03) and follicle-stimulating hormone (ptrend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment.
The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.
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OBJECTIVE: To study concordance rates of cryptorchidism (undescended testis) in pairs of boys with varying family structure, to evaluate the risk contribution from the intrauterine environment and genetic factors. DESIGN: Population based study of 1,024,500 Danish boys born from January 1, 1973 to December 31, 2004. Classic twin method and computerized square dance design. SETTING: Hospitals and outpatient clinics. PATIENT(S): Six groups of boy pairs: boys with no relation, paternal half-brothers, maternal half-brothers, full brothers, dizygotic twin brothers, and monozygotic twin brothers. INTERVENTION(S): Observational study. MAIN OUTCOME MEASURE(S): Status on each individual regarding cryptorchidism and orchiopexy from the Danish National Patient Register. RESULT(S): Concordance rates of cryptorchidism in the groups were as follows: boys with no relation 3.2% (95% confidence interval 2.7%-3.6%), paternal half-brothers 3.4% (2.3%-4.7%), maternal half-brothers 6.0% (4.5%-7.7%), full brothers 8.8% (8.3%-9.8%), dizygotic twin brothers 24.1% (16.0%-33.6%), and monozygotic twin brothers 27.3% (15.5%-41.2%). CONCLUSION(S): The concordance rate was higher in maternal than in paternal half-brothers, and much higher but of equal magnitude in both twin groups. The findings strongly support that the intrauterine environment and maternal inheritance are contributing to the occurrence of cryptorchidism.
Unit of Cellular & Molecular Toxicology, Department of Environmental and Occupational Medicine, Institute of Public Health, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark. email@example.com
Persistent organic pollutants (POPs) such as polychlorinated dibenzo-p-dioxins/furans, polychlorinated biphenyls (PCBs) and organochlorine pesticides can cause a series of adverse effects on e.g. reproduction in animals and humans, many of which involve the aryl hydrocarbon receptor (AhR). The aim of the present study was to compare the integrated serum level of AhR mediated activity among European and Inuit populations, and evaluate whether the activity was associated to the selected POP markers, 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE).
The study included 338 males from Greenland (Inuit's), Sweden, Warsaw (Poland) and Kharkiv (Ukraine). The AhR transactivity of serum extracts alone (AhRag) and competitive AhR activity (AhRcomp) upon co-exposure with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were determined in the lipophilic serum fraction containing the POPs using the AhR mediated luciferase reporter Hepa1.12cR cell assay.
The European groups showed higher median level of AhR-TEQ (TCDD toxic equivalents) compared to the Inuit's, whereas higher incidence of Inuits sample further induced AhRcomp activity. Neither AhRag nor AhR-TEQ were correlated to CB-153 or p,p'-DDE for any of the study groups. Multiple regressions showed a significant heterogeneity of association between the CB-153 and the AhRcomp across the study groups, and accordingly a negative association between AhRcomp and CB-153 was found for the Kharkiv group.
No consistent correlation between AhR activities and two POP markers was found. Although the difference of AhRag between European and Inuit men could not be explained by CB-153 or p,p'-DDE levels alone, we believe that the variation of AhR serum activity reflects different pattern of POP exposure, genetics and/or life style factors.
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 (?=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (?=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.
BACKGROUND: Persistent organochlorine pollutants (POPs) may interfere with reproductive function but direct evidence in humans is very limited. METHODS: Fertility was examined in four regions with contrasting blood levels of POPs. Pregnant women and their partners in Warsaw (Poland), Kharkiv (Ukraine) and Greenland were consecutively enrolled during antenatal visits. Swedish fishermen and their spouses were recruited separately and independently of current pregnancy. Lipid adjusted serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (DDE) were available for both partners. Time to pregnancy interviews were obtained among 2269 women and 798 men provided a semen sample. RESULTS: Inuits had high levels of both POP markers, Swedish fishermen were high in CB-153 but low in DDE, men from Kharkiv were high in DDE and low in CB-153 while men from Warsaw were low in CB-153 and had intermediate DDE levels. Compared to Warsaw couples, fecundability was reduced among couples from Kharkiv [adjusted fecundability ratio (FR) 0.64 (95% CI 0.5-0.8)] and elevated in Swedish fishermen families [FR 1.26 (95% CI 1.0-1.6)]. Adjusted geometric means of sperm counts and morphology did not differ between regions while sperm motility was higher in men living in Warsaw. CONCLUSION: We observed regional differences in time to pregnancy and sperm motility that may be related to regional differences in POP blood levels, but other interpretations are also plausible. In particular, differences in access to safe contraception and in the prevalence of contraceptive failures are most likely to bias comparisons of time to pregnancy.
Fetal loss and maternal serum levels of 2,2',4,4',5,5'-hexachlorbiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) exposure: a cohort study in Greenland and two European populations.
BACKGROUND: In the present study, the aim is to examine the risk of fetal loss related to environmental 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) or 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) exposure. METHODS: We related LC/MS/MS measurements of CB-153 and p,p'-DDE in serum samples to interview-data on previous fetal loss in populations of pregnant women from Poland, Ukraine and Greenland. RESULTS: In total, 1710 women were interviewed, and 678 of these had at least one previous pregnancy. The risk of ever experiencing a fetal loss increased at higher levels of CB-153 and p,p'-DDE exposure, with an adjusted odds ratio (OR) of 2.4; confidence interval (CI) (1.1-5.5) for CB-153>200 ng/g lipid compared to 0-25 ng CB-153/g lipid and OR of 2.5 CI (0.9-6.6) for p,p'-DDE>1500 ng/g lipid compared to 0-250 ng DDE/g lipid. However, no clear dose response associations were observed. The results further suggest that high level of organochlorine serum concentrations may be related to repeated loss. CONCLUSIONS: The risk of fetal loss may increase at higher levels of CB-153 and p,p'-DDE exposure, although lack of dose response and inconsistencies between countries did not allow for firm conclusions.