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This study examines possible associations of maternal Persistent Organic Pollutants (POP) exposure during pregnancy, maternal hormone levels and fetal growth indices (FGI). During 1st trimester, we measured maternal thyroids, androgens and estrogens, lipophilic POP and perfluorinated-alkyl-acid (PFAA) levels in serum from nulliparous women. Adjusted multivariate-linear regression models assessed associations between exposure and outcomes. Maternal characteristics and POP exposures associated with maternal hormone levels. Lipophilic POP elicited inverse association with androgen and estrogen levels but no strong association with thyroids. Higher levels of PFAA was associated with higher thyroid and androgen levels. The PFAA associated not with estrogens. Higher thyroid-peroxidase-antibody (TPO-Ab) and estradiol level associated with higher birth weight and length in sons. For daughters, the TPO-Ab associations were the opposite being inversely associated with birth weight and length, and higher TPO-Ab and estradiol associated with lower gestational age. Mediation analyses suggested that TPO-Ab mediates the association of PFAA with FGI.

Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of vali- dated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxi- cological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′ -deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU con- firms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better un- derstand the public health implications of human exposure to environmental chemicals., European Union’s Horizon 2020 research and innovation program projects HBM4EU 733032

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA., European Commission 733032 857560 101057014, Ministry of Education, Youth and Sports by the RECETOX Research Infrastructure LM2018121, OP RDE project CETOCOEN Excellence CZ.02.1.01/0.0/0.0/17_043/0009632, Japan Agency for Medical Research and Development (AMED) JP21mk0101216 JP22mk0101216, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT), Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) 21K12133

Several studies have found aberrant DNA methylation levels in breast cancer cases, but factors influencing DNA methylation patterns and the mechanisms are not well understood. This case–control study evaluated blood methylation level of two repetitive elements and selected breast cancer‐related genes in relation to breast cancer risk, and the associations with serum level of persistent organic pollutants (POPs) and breast cancer risk factors in Greenlandic Inuit. DNA methylation was determined using bisulphite pyrosequencing in blood from 74 breast cancer cases and 80 controls. Using first tertile as reference, the following was observed. Positive associations for ATM in second tertile (OR: 2.33, 95% CI: 1.04; 5.23) and ESR2 in third tertile (OR: 2.22, 95% CI: 0.97; 5.05) suggest an increased breast cancer risk with high DNA methylation. LINE‐1 methylation was lower in cases than controls. In third tertile (OR: 0.42, 95% CI: 0.18; 0.98), associations suggest in accordance with the literature an increased risk of breast cancer with LINE‐1 hypomethylation. Among controls, significant associations between methylation levels and serum level of POPs and breast cancer risk factors (age, body mass index, cotinine level) were found. Thus, breast cancer risk factors and POPs may alter the risk through changes in methylation levels; further studies are needed to elucidate the mechanisms.

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), organchlorine pesticides and perfluoroalkylated substances (PFASs) and heavy metals bioaccumulate in the marine food chain in the Arctic regions, and thus, the Greenlandic population has a higher body burden due to relatively high intake of marine mammals. We assessed the temporal trend for POPs, including PCB 153, 1,1-dichloro−2,2-bis (p-chlorophenyl)-ethylene (p,p’-DDE), oxychlordane, six PFASs, mercury, lead and selenium in Inuit from Ilulissat, Nuuk, and across Greenland (including thirteen towns/districts), from 1994 to 2015. Data showed a significant annual decrease of 6.85–8.61% for PCB153, 6.67–8.61% for p,p’-DDE, 6.11–9.52% for oxychlordane, 5.92–6.76% for mercury and 6.48–9.43% for lead in Inuit women from Nuuk, Ilulissat, and across thirteen Greenlandic districts. The blood selenium level of all Greenlandic women increased 1.01% annually, while the trend direction was negative for Nuuk women. A similar pattern was seen for men across Greenland, with a yearly decrease of 11.3% for PCB 153, 8.61% for p,p’-DDE, 15.6% for oxychlordane, 13.1% for mercury and 12.2% for lead. Perfluorooctane sulfonate, perfluorohexane sulfonate and perfluorooctanoic acid significantly decreased 5.82–11.7% annually for both women and men across Greenland. For perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid, we observed an increasing trend for women across Greenland. In conclusion, there was a decreasing trend of the regulated POPs and metals but a potential increasing trend of the nonregulated PFASs in the Greenlandic population between 1994 and 2015. The continuing biomonitoring of contaminants of concern is important to protect the Arctic population heath.

High concentrations of persistent organic pollutants (POPs) in blood of the Greenlandic population are well known. The exposure is mainly through traditional food intake, including marine mammals and seabirds. The present study aimed to follow up on POP concentrations (organochlorine pesticides, polychlorinated biphenyls, per- and polyfluoroalkyl substances, and halogenated flame retardants (HFRs)) and relations to lifestyle and diet of the mothers included in the Greenlandic ACCEPT cohort (3-5 years after inclusion in 2013-15) and to include the children's fathers. This new data collection in 2019-20 included blood samples for measurement of POP concentrations and lifestyle and food frequency questionnaires from 101 mothers and 76 fathers aged 24-55 years living in Nuuk, Sisimiut, and Ilulissat, Greenland. The mothers' intra-individual median percentage decrease in POP concentrations from inclusion to this follow-up (3-5 years later) was 16-58%, except for mirex (0% change). Median concentrations of POPs were 1.4-4.6 times higher in fathers than in mothers. The POPs differed by residential town with generally higher concentrations in Ilulissat compared to Sisimiut and Nuuk. We report, for the first time, novel HFRs in human samples from Greenland. However, concentrations were low and only dechlorane plus (with its anti-isomer) was detected in >50% of the samples. Most POPs correlated positively with age and n-3/n-6 fatty acid ratio. The lipophilic POPs correlated positively with the percentage of life lived in Greenland, whereas few POPs correlated positively with BMI, income (personal and household), education, and alcohol intake. The POPs generally associated positively with the intake of marine mammals, seabirds, and dried fish, while few POPs associated positively with Greenlandic fish intake. In contrast, POPs generally associated negatively with imported meat products intake. The study findings may be of interest for future dietary recommendations in Greenland. We discuss the potential explanations for the findings and suggestions for future research.

To investigate the transplacental transport of pesticides, the pyrethroid cypermethrin and the fungicide azoles, propiconazole and bitertanol were tested in the placental perfusion model. Cypermethrin, propiconazole and bitertanol were also tested in the BeWo cell transfer model. The pesticides were chosen with the selection criteria: use in Denmark, significant treated areas and knowledge on hormone‐disrupting effects. Propiconazole and bitertanol showed rapid transfer and adsorbance to the system in both placental perfusion and BeWo cell system, whereas cypermethrin had a slower transport across the placental cell layers in the two models. There was no difference between data of the single pesticides and their mixture in either placental perfusion or BeWo cell transfer model. Both the placental perfusion model and the BeWo cell model metabolized the pesticides and released metabolites into both foetal and maternal circulation. Using human exposure models, this study shows the potential exposure of the human foetus to pesticides cypermethrin, propiconazole and bitertanol and their metabolites.

This chapter describes the evidence of early-life environmental influences on growth and development. The most environmental influences discussed include the exposure to pesticides, endocrine-disrupting chemicals (EDCs), metals, and persistent organic pollutants (POPs). The exposure outcome focused includes obesity, asthma, allergies, neurodevelopmental disorders, during gestation, infancy and childhood, and/or reproductive development later in life. EDCs have been reported to act as an agonist or antagonists of the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR). Other mechanisms such as oxidative stress and DNA alterations and inflammation also play important roles in effect of the early exposure to environmental contaminants on growth and development. In this chapter, the combined effect of all the compounds present in the human body was also emphasized to be considered for risk assessment.

The Greenlandic population has some of the highest levels of environmental persistent organic pollutants (POPs) globally. Studies have previously found POPs to be linked with disturbance of child development, immune function and reproductive abilities. We investigated the associations between serum POP levels of pregnant women in Greenland and their infant's birth weight, length, head circumference and gestational age (GA) at birth. Pregnant Greenlandic women (n = 504) were enrolled during pregnancy and serum levels of the lipophilic POPs (Organochlorine pesticides, Polychlorinated biphenyls and Polybrominated diphenyl ethers) and the amphiphilic POPs, Perfluoroalkylated substances (PFASs), were measured. We analysed the associations between maternal serum levels of POPs and birth weight, length, head circumference and GA using linear regression analysis. We found significant inverse associations between Perfluorooctanoic Acid (PFOA) and birth weight (adjusted β = −119 g, 95% CI: −201; −36), birth length (adjusted β = −0.37 cm, 95% CI: −0.76; 0.02, borderline significant) and head circumference (adjusted β = −0.35 cm, 95% CI: −0.59; −0.10) and a positive association with GA (adjusted β = 0.45 week, 95% CI: 0.17; 0.74). For the lipophilic POPs, we found an overall trend of inverse associations to foetal growth indices. In conclusion, we found that the amphiphilic PFOA had a significant inversely association with foetal growth indices, whereas GA was positively associated. The data indicate that POPs have a negative effect on foetal growth.

Adjusted odds ratio and 95% confidence intervals for ASD according to hormone level and receptor transactivity induced by amniotic fluid stratified by gender. (DOCX 19 kb)

Adjusted odds ratio and 95% confidence intervals for ASD according to PCA component after removing congenital malformation. (DOCX 17 kb)

Adjusted odds ratio and 95% confidence intervals for ASD according to PCA component stratified by gender. (DOCX 17 kb)

BACKGROUND:Higher concentrations of single perfluorinated alkyl acids (PFAAs) have been associated with lower birth weight (BW), but few studies have examined the combined effects of PFAA mixtures. PFAAs have been reported to induce estrogen receptor (ER) transactivity, and estrogens may influence human fetal growth. We hypothesize that mixtures of PFAAs may affect human fetal growth by disrupting the ER.OBJECTIVES:We aimed to study the associations between the combined xenoestrogenic activity of PFAAs in pregnant women's serum and offspring BW, length, and head circumference.METHODS:We extracted the actual mixture of PFAAs from the serum of 702 Danish pregnant women (gestational wk 11-13) enrolled in the Aarhus Birth Cohort (ABC) using solid phase extraction, high-performance liquid chromatography (HPLC), and weak anion exchange. PFAA-induced xenoestrogenic receptor transactivation (XER) was determined using the stable transfected MVLN cell line. Associations between XER and measures of fetal growth were estimated using multivariable linear regression with primary adjustment for maternal age, body mass index (BMI), educational level, smoking, and alcohol intake, and sensitivity analyses with additional adjustment for gestational age (GA) (linear and quadratic).RESULTS:On average, an interquartile range (IQR) increase in XER was associated with a [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] decrease in BW and a [Formula: see text] (95% CI: 0.1, 0.5) decrease in birth length. Upon additional adjustment for GA, the estimated mean differences were [Formula: see text] (95% CI: [Formula: see text], 4) and [Formula: see text] (95% CI: [Formula: see text], 0.0), respectively.CONCLUSION:Higher-serum PFAA-induced xenoestrogenic activities were associated with lower BW and length in offspring, suggesting that PFAA mixtures may affect fetal growth by disrupting ER function. https://doi.org/10.1289/EHP1884.

The percentage of elements in the amniotic fluid samples which were above the detection limit. (DOCX 18 kb)

Descriptive statistics for the exposure biomarkers with detection frequency > 10% in amniotic fluid and used in the principal component analysis. (DOCX 17 kb)

Adjusted odds ratio and 95% confidence intervals for ASD according to chemicals, hormone level and receptor transactivity induced by amniotic fluid after removing congenital malformation. (DOCX 23 kb)

Environmental contaminants such as heavy metals are transported to the Arctic regions via atmospheric and ocean currents and enter the Arctic food web. Exposure is an important risk factor for health and can lead to increased risk of a variety of diseases. This study investigated the association between pregnant women’s levels of heavy and essential metals and the birth outcomes of the newborn child. This cross-sectional study is part of the ACCEPT birth cohort (Adaption to Climate Change, Environmental Pollution, and dietary Transition) and included 509 pregnant Inuit women ≥18 years of age. Data were collected in five Greenlandic regions during 2010–2015. Population characteristics and birth outcomes were obtained from medical records and midwives, respectively, and blood samples were analyzed for 13 metals. Statistical analysis included one-way ANOVA, Spearman’s rho, and multiple linear and logistic regression analyses. The proportion of current smokers was 35.8%. The levels of cadmium, chromium, and nickel were higher compared to reported normal ranges. Significant regional differences were observed for several metals, smoking, and parity. Cadmium and copper were significantly inversely related to birth outcomes. Heavy metals in maternal blood can adversely influence fetal development and growth in a dose–response relationship. Diet and lifestyle factors are important sources of toxic heavy metals and deviant levels of essential metals. The high frequency of smokers in early pregnancy is of concern, and prenatal exposure to heavy metals and other environmental contaminants in the Greenlandic Inuit needs further research.

Adjusted odds ratio and 95% confidence intervals for ASD according to chemicals in amniotic fluid stratified by gender. (DOCX 20 kb)

Level of PCA scores. (DOCX 18 kb)

The percentage of PFAS in the amniotic fluid samples which were above the detection limit. (DOCX 26 kb)

BACKGROUND: During past decades the formerly active lifestyle in Greenland has become sedentary, and the intake of traditional food has gradually been replaced with imported food. These lifestyle and dietary habits may affect pregnant women. AIM: To describe age and regional differences in reproductive factors, lifestyle and diet among Greenlandic pregnant women in their first trimester. METHODS: A cross-sectional study during 2013-2015 including 373 pregnant women was conducted in five Greenlandic regions (West, Disko Bay, South, North and East). Interview-based questionnaires on reproductive factors, lifestyle and dietary habits were compared in relation to two age groups (median age ≤28 years and >28 years). RESULTS: In total, 72.4% were Inuit, 46.6% had BMI >25.0 kg/m2, 29.0% were smoking during pregnancy and 54.6% had used hashish. BMI, educational level, personal income, previous pregnancies and planned breastfeeding period were significantly higher in the age group >28 years of age compared to the age group ≤28 years of age. In region Disko Bay, 90.9% were Inuit, in region South more had a university degree (37.9%) and region East had the highest number of previous pregnancies, the highest number of smokers during pregnancy and the most frequent intake of sauce with hot meals and fast-food. CONCLUSIONS: Overall a high BMI and a high smoking frequency were found. Age differences were found for BMI and planned breastfeeding period, while regional differences were found for smoking and intake of sauce with hot meals and fast-food. Future recommendations aimed at pregnant women in Greenland should focus on these health issues. BACKGROUND: During past decades the formerly active lifestyle in Greenland has become sedentary, and the intake of traditional food has gradually been replaced with imported food. These lifestyle and dietary habits may affect pregnant women. AIM: To describe age and regional differences in reproductive factors, lifestyle and diet among Greenlandic pregnant women in their first trimester. METHODS: A cross-sectional study during 2013-2015 including 373 pregnant women was conducted in five Greenlandic regions (West, Disko Bay, South, North and East). Interview-based questionnaires on reproductive factors, lifestyle and dietary habits were compared in relation to two age groups (median age ≤28 years and >28 years). RESULTS: In total, 72.4% were Inuit, 46.6% had BMI >25.0 kg/m2, 29.0% were smoking during pregnancy and 54.6% had used hashish. BMI, educational level, personal income, previous pregnancies and planned breastfeeding period were significantly higher in the age group >28 years of age compared to the age group ≤28 years of age. In region Disko Bay, 90.9% were Inuit, in region South more had a university degree (37.9%) and region East had the highest number of previous pregnancies, the highest number of smokers during pregnancy and the most frequent intake of sauce with hot meals and fast-food. CONCLUSIONS: Overall a high BMI and a high smoking frequency were found. Age differences were found for BMI and planned breastfeeding period, while regional differences were found for smoking and intake of sauce with hot meals and fast-food. Future recommendations aimed at pregnant women in Greenland should focus on these health issues.

The Greenlandic Inuit have high blood concentrations of environmental persistent organic pollutants (POPs). High POP concentrations have been associated with age, smoking and consumption of marine mammals. Studies have indicated that exposure to POPs during pregnancy may adversely affect fetal and child development. To assess geographical differences in diet, lifestyle and environmental contaminant exposure among pregnant women in Greenland, blood samples and questionnaire data were collected from 207 pregnant women in five Greenlandic regions (North, Disco Bay, West, South and East). Blood samples were analyzed for 11 organochlorine pesticides (OCPs), 14 polychlorinated biphenyls (PCBs), 5 polybrominated diphenyl ethers (PBDEs), 15 perfluoroalkylated substances (PFASs) and 63 metals. A trend of higher intake of marine mammals in the East and North regions was reflected by a higher n-3/n-6 fatty acid ratio. Participants in the East region tended also to have higher intake of terrestrial species. A significant higher seabird intake was seen for pregnant women in the West region. Significant regional differences were found for blood concentrations of PCBs, OCPs, PFASs and mercury, with higher levels in the North and East regions. PFASs were significantly associated with PCBs and OCPs in most of the regions. In the North region, PFASs were associated with both selenium and mercury. No significant regional difference was observed for PBDEs. The regional differences of blood levels of POPs and mercury were related to differences in intake of the traditional food. Compared to earlier reports, decreased levels of legacy POPs, Hg and Pb and perfluorooctane sulfonate and perfluorooctanoic acid were observed, but the levels of PFAS congeners perfluorohexane sulfonate and perfluorononanoic acid were sustained. The detection of POPs and heavy metals in maternal blood indicates fetal exposure to these compounds possibly influencing fetal development.

Evidence suggest that exposure to pesticides can interfere with the endocrine system by multiple mechanisms. The endocrine disrupting potential of currently used pesticides in Denmark was analyzed as single compounds and in an equimolar mixture of 5 selected pesticides. The pesticides were previously analyzed for effects on the function of estrogen and androgen receptors, the aromatase enzyme and steroidogenesis in vitro. In this study, the effect on thyroid hormone (TH) function and aryl hydrocarbon receptor (AhR) transactivity was assessed using GH3 cell proliferation assay (T-screen) and AhR responsive luciferase reporter gene bioassay, respectively. Thirteen pesticides were analyzed as follows: 2-methyl-4-chlorophenoxyacetic acid, terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb and its metabolite ethylene thiourea, cypermethrin, tau-fluvalinate, and malathion (currently banned in DK). In the T-screen, prothioconazole, malathion, tau-fluvalinate, cypermethrin, terbuthylazine and mancozeb significantly stimulated and bitertanol and propiconazole slightly reduced the GH3 cell proliferation. In the presence of triiodothyronine (T3), prothioconazole, tau-fluvalinate, propiconazole, cypermethrin and bitertanol significantly antagonized the T3-induced GH3 cell proliferation. Eleven of the tested pesticides agonized the AhR function, and bitertanol and prothioconazole inhibited the basal AhR activity. Bitertanol, propiconazole, prothioconazole and cypermethrin antagonized the TCDD-induced AhR transactivation at the highest tested concentration. The 5-component mixture had inducing effect but the combined effect could not be predicted due to the presence of bitertanol eliciting inhibitory effect. Upon removal of bitertanol from the mixture, the remaining four pesticides acted additively. In conclusion, our data suggest that pesticides currently used in Denmark can interfere with TH signaling and AhR function in vitro and might have the potential to cause endocrine disruption.

In the present case-cohort study based on prospective data from Danish women, we aimed to estimate the main effect of polymorphisms in genes known to be involved in the steroid hormone metabolic pathway and xenobiotic metabolism on the risk of developing breast cancer. We also studied a possible effect measure modification between genotypes and levels of serum perfluoroalkylated substances (PFASs) on the risk to breast cancer. We have previously reported a weak association between serum PFASs levels and the risk of breast cancer for this study population of Danish pregnant nulliparous women as well as in a smaller case-control study of Greenlandic women. The study population consisted of 178 breast cancer cases and 233 controls (tabnulliparous and frequency matched on age) nested within the Danish National Birth Cohort (DNBC), which was established in 1996-2002. Blood samples were drawn at the time of enrollment (6-14 week of gestation). Serum levels of 10 perfluorocarboxylated acids (PFCAs), 5 perfluorosulfonated acids (PFSAs) and 1 sulfonamide (perflurooctane-sulfonamide, PFOSA) were measured. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1→ A2; rs743572); CYP19A1 (C→T; rs10046) by the TaqMan allelic discrimination method. In overall, no significant associations were found between the investigated polymorphisms and the risk of breast cancer in this study among Danish women. The previously found association between PFOSA and risk of breast cancer did vary between different genotypes, with significantly increased risk confined to homozygous carriers of the following alleles: COMT (Met), CYP17 (A1) and CYP19 (C).CONCLUSION: Our results indicate that polymorphisms in COMT, CYP17 and CYP19 which are involved in estrogen biosynthesis and metabolism can modulate the potential effects of PFOSA exposure on the development of breast cancer.

Background Perfluoroalkyl acids (PFAAs) are persistent and bioaccumulating compounds, which are spread all over the globe. We aimed to compare the PFAA concentrations in serum from pregnant women in five birth cohorts from four countries (Denmark, China, Norway, and Greenland). Methods Serum samples were obtained from the following five birth cohorts including a total of 4718 pregnant women: the Danish National Birth Cohort (DNBC, years 1996–2002, Denmark), the Aarhus Birth Cohort (ABC, years 2008–2013, Denmark), the Shanghai Birth Cohort (SBC, years 2013–2015, China), the Northern Norway Mother-Child Contaminant Cohort (MISA, years 2007–2009, Norway), and the Greenlandic Birth Cohort (ACCEPT, years 2010–2013, Greenland). The samples were analyzed using liquid chromatography triple–quadrupole mass spectrometry. To ensure comparability, all samples except for the MISA samples were measured in the same laboratory. We adjusted the log-transformed PFAA concentrations for age and parity using analysis of covariance. Results and discussion The geometric mean (GM) of the summed concentrations of the seven most abundant PFAAs (∑PFAA) was 35 ng/mL in the DNBC, 25 ng/mL in the SBC, 18 ng/mL in the ACCEPT, 12 ng/mL in the MISA cohort, and 12 ng/mL in the ABC. The DNBC concentration was highest presumably because these samples were taken in earlier years (i.e. 1996–2002) than the samples from the other cohorts (i.e. 2007–2015), and at a time when the production of PFAAs were at the highest. When excluding the DNBC samples, we found that the concentrations of all the perfluorinated sulfonic acids (PFSAs) and one of the four perfluorinated carboxylic acids (PFCAs) were highest in the Greenlandic women, whereas the other three PFCAs were highest in the Chinese women. Conclusion The concentration and composition of serum PFAAs were similar for the Danish ABC women and the Norwegian MISA women but were otherwise different across the cohorts. The different exposure profiles might partly be related to differences in lifestyle and diet. As the concentrations and compositional patterns vary between the countries, we suggest that the health implications associated with high PFAA exposure might also differ between the countries.

Effluents from municipal wastewater-treatment plants and scattered dwellings, as well as runoff from agricultural fields, are sources of endocrine-disrupting compounds (EDCs) in the aquatic environment. The present study investigated the correlation between the occurrence of EDCs in nine Danish streams using passive samplers (polar organic integrative samplers and silicone membranes) and determined their possible biological effects as assessed by mammal cell cultures and the mussel (Unio tumidus). The passive samplers and mussels were exposed simultaneously at the study sites. The extracts from the passive samplers were used to measure the concentrations of EDCs and the biological effects on the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR)-receptor transactivation. Male mussels were investigated for biomarkers of endocrine effects, such as the levels of vitellogenin-like proteins measured as alkali-labile phosphate (ALP). EDC concentrations, hormone-receptor transactivation (ER, AR, AhR), and level of ALP were greater downstream of wastewater-treatment plants compared with upstream sites and sites supposed to be relatively nonimpacted by wastewater. Furthermore, there was a significant positive correlation between in vitro AhR transactivation and frequency of ALP of male mussels. We conclude that wastewater effluent is an important source of endocrine-disrupting effects in the aquatic environment and that the combination of biological effect measurements and chemical analyses based on passive sampling is useful in the assessment of the ecological state of the aquatic environment.

Perfluoroalkyl acids (PFAAs) are perfluorinated compounds that widely exist in the environment and can elicit adverse effects including endocrine disruption in humans and animals. This study investigated the effect of seven PFAAs on the thyroid hormone (TH) system assessing the proliferation of the 3,3',5-triiodo-L-thryonine (T3)-dependent rat pituitary GH3 cells using the T-screen assay and the effect on the aryl hydrocarbon receptor (AhR) transactivation in the AhR-luciferase reporter gene bioassay. A dose-dependent impact on GH3 cells was observed in the range 1 × 10(-9)-1 × 10(-4) M: seven PFAAs (perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), and perfluorododecanoic acid (PFDoA)) inhibited the GH3 cell growth, and four PFAAs (PFOS, PFHxS, PFNA, and PFUnA) antagonized the T3-induced GH3 cell proliferation. At the highest test concentration, PFHxS showed a further increase of the T3-induced GH3 growth. Among the seven tested PFAAs, only PFDoA and PFDA elicited an activating effect on the AhR. In conclusion, PFAAs possess in vitro endocrine-disrupting potential by interfering with TH and AhR functions, which need to be taken into consideration when assessing the impact on human health.

The aim of this study was to investigate the spatial distribution, levels of dioxin-like compounds (DLC), and biological responses in two fish species. The viviparous eelpout (Zoarces viviparus) was collected from various locations in the Baltic Sea and in fjords of Kattegat and Skagerrak, while shorthorn sculpin (Myoxocephalus scorpius) was obtained at the polychlorinated biphenyl (PCB) polluted site in North West Greenland. Significant differences were detected both in contaminant levels and relative contributions from either polychlorinated dibenzodioxins (PCDD) or polychlorinated dibenzofurans (PCDF or furans) and mono-ortho- and non-ortho (coplanar) polychlorinated biphenyls (dl-PCB). Fish from the eastern Baltic Sea generally displayed higher contributions from PCDD/F compared to dl-PCB, whereas dl-PCB were generally predominated in fish from Danish, Swedish, and German sites. Levels of dl-PCB in muscle tissues were above OSPAR environmental assessment criteria (EAC) for PCB118, indicating a potential risk of adverse biological effects in the ecosystem, whereas levels of the total WHO-TEQs were below threshold for sea food suggesting limited risks for humans. No significant relationships between levels of DLC (expressed as WHO-TEQ), and biological responses such as the induction of CYP1A enzymatic activity and fry reproductive disorders were observed in eelpout. No marked relationship between WHO-TEQ and combined biological aryl hydrocarbon receptor-mediated transactivity (expressed as AhR-TEQ) was noted. However, there was a positive correlation between polycyclic aromatic hydrocarbon (PAH) metabolites and induction of CYP1A activity, suggesting that PAH exhibited greater potential than DLC to produce biological effects in eelpout from the Baltic Sea.

© 2017, Springer-Verlag Berlin Heidelberg. The use of the lipophilic persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs) and several organochlorine pesticides (OCPs) has been prohibited for more than 30 years. In this study, we present the temporal trends of the lipophilic POP serum concentrations in Danish nulliparous pregnant women between 2011 and 2013. We randomly selected 197 pregnant women (gestational age 11–13) from the Aarhus Birth Cohort. The concentrations of the lipophilic POPs in the serum samples were analyzed using gas chromatography. The concentrations were corrected for total serum lipids. The statistical analysis was performed by regression analysis with adjustment for age, BMI, gestational age at blood draw, and smoking status. The serum concentrations of PCB 118, 138, 153, 156, 170, 180, 187, and hexachlorobenzen, trans-nonachlor, β-hexachlorocyclohexane (β-HCH), and p,p’-dichlorodiphenyldichloroethylene were lower in 2013 than in 2011. However, the oxychlordane concentration was lowest in 2011. The serum levels of most lipophilic POPs followed downward trends during the study period, which was expected, as these compounds has been banned for many years. The upward trend of oxychlordane was unexpected and presumably a chance finding.