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Article ; Online: Neonatal gut and immune responses to beta-casein enriched formula in piglets.

Holgersen, Kristine / Muk, Tik / Ghisari, Mandana / Arora, Pankaj / Kvistgaard, Anne Staudt / Nielsen, Søren Drud-Heydary / Sangild, Per Torp / Bering, Stine Brandt

The Journal of nutrition

2024

Abstract: Background: β-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less β-casein than HM, but whether different levels of β- ... ...

Abstract	Background: β-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less β-casein than HM, but whether different levels of β-casein affect tolerability and gut and immune maturation in newborns is unknown. Objective: Using near-term piglets as a model for newborn infants, we investigate whether increasing the β-casein fraction in bovine-based formula is clinically safe and may improve gut and immune maturation. Methods: Three groups of near-term pigs (96% gestation) were fed formula with bovine casein and whey protein (ratio 40:60): 1) Standard skim milk casein (BCN-standard, 35% β-casein of total casein, n=18), 2) β-casein enrichment to HM levels (BCN-medium, 65%, n=19), and 3) high β-casein enrichment (BCN-high, 91%, n=19). A reference group was fed 100% whey protein concentrate as protein (WPC, n=18). Intestinal and immune parameters were assessed before and after euthanasia on day 5. Results: Clinical variables (mortality, activity, body growth, diarrhea) were similar among the groups, and no differences in intestinal or biochemical parameters were observed between BCN-standard and BCN-medium pigs. However, pigs receiving high amounts of β-casein (BCN-high) had lower small intestine weight, and tended to have more intestinal complications (highest gut pathology score, permeability, IL-8) than the other groups, particularly those receiving no casein (WPC pigs). Blood lymphocyte, thrombocyte and reticulocyte counts were increased with higher β-casein, while eosinophil counts were reduced. In vitro blood immune cell responses were similar among groups. Conclusions: β-casein enrichment of bovine-based formula to HM levels is clinically safe, as judged from newborn, near-term pigs, while no additional benefits to gut maturation were observed. However, excessive β-casein supplementation, beyond levels in HM, may potentially induce gut inflammation together with increased blood cell populations relative to natural β-casein levels or pure whey-based formula.
Language	English
Publishing date	2024-05-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	218373-0
ISSN	1541-6100 ; 0022-3166
ISSN (online)	1541-6100
ISSN	0022-3166
DOI	10.1016/j.tjnut.2024.04.036
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Article ; Online: Genetic Variations, Exposure to Persistent Organic Pollutants and Breast Cancer Risk - A Greenlandic Case-Control Study.

Wielsøe, Maria / Eiberg, Hans / Ghisari, Mandana / Kern, Peder / Lind, Ole / Bonefeld-Jørgensen, Eva Cecilie

Basic & clinical pharmacology & toxicology

2018 Volume 123, Issue 3, Page(s) 335–346

Abstract: This study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone-metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and ... ...

Abstract	This study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone-metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and breast cancer associations. The study also assessed effects of Greenlandic BRCA1 founder mutations. Greenlandic Inuit women (77 cases and 84 controls) were included. We determined two founder mutations in BRCA1: Cys39Gly (rs80357164) and 4684delCC, and five SNPs in xenobiotic and oestrogen-metabolizing genes: CYP17A1 -34T>C (rs743572), CYP19A1 *19C>T (rs10046), CYP1A1 Ile462Val (rs1048943), CYP1B Leu432Val (rs1056836) and COMT Val158Met (rs4680). We used chi-square test for comparison of categorical variables between groups. Odds ratio (OR) estimates with 95% confidence interval (95%CI) were obtained using logistic regression models. The variant allele of BRCA1 Cys39Gly increased breast cancer risk (Gly/Cys versus Cys/Cys, OR: 12.2, 95%CI: 1.53; 98.1), and carriers of the variant allele of CYP17A1 -34T>C had reduced risk (CT+CC versus TT, OR: 0.44, 95%CI: 0.21; 0.93). CYP17A1 -34T>C was an effect modifier on the association between perfluoroalkyl acids (PFAAs) and breast cancer risk (∑PFAA, ratio of OR: 0.18, 95%CI: 0.03; 0.97). Non-significant modifying tendencies were seen for the other SNPs on the effect of polychlorinated biphenyls, organochlorine pesticides and PFAAs. In summary, the BRCA1 Cys39Gly and CYP17A1 -34T>C genetic variations were associated with breast cancer risk. Our results indicate that the evaluated genetic variants modify the effects of POP exposure on breast cancer risk; however, further studies are needed to document the data from the relatively small sample size.
MeSH term(s)	Adult ; Aged ; BRCA1 Protein/genetics ; Breast Neoplasms/epidemiology ; Breast Neoplasms/etiology ; Breast Neoplasms/genetics ; Case-Control Studies ; Cytochrome P-450 Enzyme System/genetics ; Environmental Exposure/adverse effects ; Environmental Pollutants/toxicity ; Female ; Founder Effect ; Genetic Predisposition to Disease ; Genetic Variation ; Greenland/epidemiology ; Humans ; Inuits ; Logistic Models ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide ; Risk
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; Environmental Pollutants ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2018-04-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2134679-3
ISSN	1742-7843 ; 1742-7835
ISSN (online)	1742-7843
ISSN	1742-7835
DOI	10.1111/bcpt.13002
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Article ; Online: Activation of the estrogen receptor by human serum extracts containing mixtures of perfluorinated alkyl acids from pregnant women.

Bjerregaard-Olesen, Christian / Ghisari, Mandana / Bonefeld-Jørgensen, Eva C

Environmental research

2016 Volume 151, Page(s) 71–79

Abstract: Humans are exposed to a wide variety of perfluorinated alkyl acids (PFAAs). Several studies have found xenoestrogenic activity of single PFAAs. Studies on mixture effects of the PFAAs are however sparse. In the present study, we aimed to determine the ... ...

Abstract	Humans are exposed to a wide variety of perfluorinated alkyl acids (PFAAs). Several studies have found xenoestrogenic activity of single PFAAs. Studies on mixture effects of the PFAAs are however sparse. In the present study, we aimed to determine the xenoestrogenic activity in human serum extracts containing mixtures of PFAAs. Recently we developed a method to extract the PFAAs from human serum with simultaneous removal of endogenous hormones and interfering steroid metabolites. We used this method to extract the PFAAs from serum of 397 Danish nulliparous pregnant women followed by analysis of estrogen receptor (ER) transactivation using MVLN cells carrying an estrogen response element luciferase reporter vector. Using 17β-estradiol (E2) concentration-transactivation curves, we calculated the estradiol equivalents (EEQ) for the extracts containing the PFAAs. Fifty-two percent of the PFAA serum extracts agonized the ER transactivation, and 46% enhanced the E2-induced ER transactivation. We found positive linear concentration-response associations between the ER transactivation and the PFAA serum levels. For the relatively few PFAA extracts that antagonized the ER in the presence of 24 pM E2 (n=38, 10%), we found inverse linear associations between the ER transactivation and the PFAA serum levels. The results indicated that the serum extracts induced the ER in a non-monotonic concentration dependent manner. The median EEQ of the extracts containing the PFAAs corresponds to the effect of 0.5pg E2 per mL serum. In conclusion, we observed that most of the extracts containing the PFAA mixtures from pregnant women's serum agonized the ER and enhanced the E2-induced effects in non-monotonic concentration-dependent manners.
MeSH term(s)	Adult ; Carboxylic Acids/blood ; Carboxylic Acids/metabolism ; Environmental Pollutants/blood ; Environmental Pollutants/metabolism ; Estradiol/metabolism ; Estrogens/metabolism ; Female ; Fluorocarbons/blood ; Fluorocarbons/metabolism ; Humans ; Pregnancy ; Receptors, Estrogen/metabolism ; Serum ; Sulfonic Acids/blood ; Sulfonic Acids/metabolism
Chemical Substances	Carboxylic Acids ; Environmental Pollutants ; Estrogens ; Fluorocarbons ; Receptors, Estrogen ; Sulfonic Acids ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2016-11
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	205699-9
ISSN	1096-0953 ; 0013-9351
ISSN (online)	1096-0953
ISSN	0013-9351
DOI	10.1016/j.envres.2016.07.001
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Article: Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort

Ghisari, Mandana / Durita Mohr Røge / Eva C. Bonefeld-Jørgensen / Jørn Olsen / Manhai Long

Environmental research. 2017 Apr., v. 154

2017

Abstract: 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 ...

Abstract	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.
Keywords	acids ; alleles ; biochemical pathways ; biosynthesis ; blood sampling ; blood serum ; breast neoplasms ; case-control studies ; estrogens ; genotyping ; homozygosity ; perfluorocarbons ; pregnancy ; risk ; steroid hormones ; women ; xenobiotics
Language	English
Dates of publication	2017-04
Size	p. 325-333.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205699-9
ISSN	1096-0953 ; 0013-9351
ISSN (online)	1096-0953
ISSN	0013-9351
DOI	10.1016/j.envres.2017.01.020
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Effects of currently used pesticides and their mixtures on the function of thyroid hormone and aryl hydrocarbon receptor in cell culture.

Ghisari, Mandana / Long, Manhai / Tabbo, Agnese / Bonefeld-Jørgensen, Eva Cecilie

Toxicology and applied pharmacology

2015 Volume 284, Issue 3, Page(s) 292–303

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation ; Denmark ; Dose-Response Relationship, Drug ; Endocrine Disruptors/toxicity ; Genes, Reporter ; Liver/drug effects ; Liver/metabolism ; Mice ; Pesticides/toxicity ; Rats ; Receptors, Aryl Hydrocarbon/drug effects ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism ; Risk Assessment ; Signal Transduction/drug effects ; Thyroid Gland/drug effects ; Thyroid Gland/metabolism ; Thyroid Gland/pathology ; Transfection ; Triiodothyronine/metabolism
Chemical Substances	Endocrine Disruptors ; Pesticides ; Receptors, Aryl Hydrocarbon ; Triiodothyronine (06LU7C9H1V)
Language	English
Publishing date	2015-05-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2015.02.004
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Article ; Online: Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro.

Wielsøe, Maria / Long, Manhai / Ghisari, Mandana / Bonefeld-Jørgensen, Eva C

Chemosphere

2015 Volume 129, Page(s) 239–245

Abstract: Perfluoroalkylated substances (PFAS) have been widely used since 1950s and humans are exposed through food, drinking water, consumer products, dust, etc. The long-chained PFAS are persistent in the environment and accumulate in wildlife and humans. They ... ...

Abstract	Perfluoroalkylated substances (PFAS) have been widely used since 1950s and humans are exposed through food, drinking water, consumer products, dust, etc. The long-chained PFAS are persistent in the environment and accumulate in wildlife and humans. They are suspected carcinogens and a potential mode of action is through generation of oxidative stress. Seven long-chained PFAS found in human serum were investigated for the potential to generate reactive oxygen species (ROS), induce DNA damage and disturb the total antioxidant capacity (TAC). The tested PFAS were perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluoroctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA). Using the human hepatoma cell line (HepG2) and an exposure time of 24h we found that all three endpoints were affected by one or more of the compounds. PFHxS, PFOA, PFOS and PFNA showed a dose dependent increase in DNA damage in the concentration range from 2×10(-7) to 2×10(-5)M determined by the comet assay. Except for PFDoA, all the other PFAS increased ROS generation significantly. For PFHxS and PFUnA the observed ROS increases were dose-dependent. Cells exposed to PFOA were found to have a significant lower TAC compared with the solvent control, whereas a non-significant trend in TAC decrease was observed for PFOS and PFDoA and an increase tendency for PFHxS, PFNA and PFUnA. Our results indicate a possible genotoxic and cytotoxic potential of the PFAS in human liver cells.
MeSH term(s)	Alkanesulfonates ; Alkanesulfonic Acids/pharmacology ; Antioxidants ; Biomarkers ; Comet Assay ; DNA Damage ; Fluorocarbons/pharmacology ; Humans ; Oxidative Stress/drug effects ; Reactive Oxygen Species
Chemical Substances	Alkanesulfonates ; Alkanesulfonic Acids ; Antioxidants ; Biomarkers ; Fluorocarbons ; Reactive Oxygen Species ; hexadecafluoro-nonanoic acid (76-21-1) ; perfluorooctane sulfonic acid (9H2MAI21CL) ; perflexane (FX3WJ41CMX)
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2014.10.014
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Zs.A 2540: Show issues

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Article ; Online: Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity.

Kjeldsen, Lisbeth Stigaard / Ghisari, Mandana / Bonefeld-Jørgensen, Eva Cecilie

Toxicology and applied pharmacology

2013 Volume 272, Issue 2, Page(s) 453–464

Abstract: The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and ... ...

Abstract	The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [(3)H](2)O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks.
MeSH term(s)	Animals ; Aromatase/metabolism ; CHO Cells ; Cell Line, Tumor ; Cell Survival/drug effects ; Complex Mixtures/chemistry ; Complex Mixtures/toxicity ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Endocrine Disruptors/chemistry ; Endocrine Disruptors/toxicity ; Humans ; Pesticides/chemistry ; Pesticides/toxicity ; Quantitative Structure-Activity Relationship ; Receptors, Androgen/biosynthesis ; Receptors, Androgen/genetics ; Receptors, Estrogen/biosynthesis ; Receptors, Estrogen/genetics ; Transcriptional Activation/drug effects
Chemical Substances	Complex Mixtures ; Endocrine Disruptors ; Pesticides ; Receptors, Androgen ; Receptors, Estrogen ; Aromatase (EC 1.14.14.1)
Language	English
Publishing date	2013-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2013.06.028
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Article ; Online: Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans.

Ghisari, Mandana / Long, Manhai / Bonefeld-Jørgensen, Eva C

International journal of circumpolar health

2013 Volume 72, Page(s) 21113

Abstract: Background: The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and ... ...

Abstract	Background: The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene-environment interactions in relation to health risks is needed. Objectives: The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. Results: The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion: Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.
MeSH term(s)	Adult ; Aged ; Arctic Regions/epidemiology ; Aryl Hydrocarbon Hydroxylases/genetics ; Catechol O-Methyltransferase/genetics ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1B1 ; European Continental Ancestry Group/genetics ; Female ; Gene Frequency ; Genotype ; Greenland/epidemiology ; Humans ; Inuits/genetics ; Male ; Middle Aged ; Polymorphism, Genetic
Chemical Substances	Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; Catechol O-Methyltransferase (EC 2.1.1.6)
Language	English
Publishing date	2013-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1386707-6
ISSN	2242-3982 ; 1239-9736
ISSN (online)	2242-3982
ISSN	1239-9736
DOI	10.3402/ijch.v72i0.21113
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Zs.A 2467: Show issues

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Article ; Online: Effects of perfluoroalkyl acids on the function of the thyroid hormone and the aryl hydrocarbon receptor.

Long, Manhai / Ghisari, Mandana / Bonefeld-Jørgensen, Eva Cecilie

Environmental science and pollution research international

2013 Volume 20, Issue 11, Page(s) 8045–8056

Abstract: 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 ( ... ...

Abstract	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.
MeSH term(s)	Animals ; Biological Assay ; Dose-Response Relationship, Drug ; Endocrine Disruptors/toxicity ; Fluorocarbons/toxicity ; Hazardous Substances/toxicity ; Rats ; Receptors, Aryl Hydrocarbon ; Risk Assessment ; Thyroid Gland/drug effects ; Thyroid Hormones/metabolism
Chemical Substances	Endocrine Disruptors ; Fluorocarbons ; Hazardous Substances ; Receptors, Aryl Hydrocarbon ; Thyroid Hormones
Language	English
Publishing date	2013-03-29
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1178791-0
ISSN	1614-7499 ; 0944-1344
ISSN (online)	1614-7499
ISSN	0944-1344
DOI	10.1007/s11356-013-1628-7
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Article ; Online: Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort.

Ghisari, Mandana / Long, Manhai / Røge, Durita Mohr / Olsen, Jørn / Bonefeld-Jørgensen, Eva C

Environmental research

2017 Volume 154, Page(s) 325–333

Abstract	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.
MeSH term(s)	Adult ; Aged ; Breast Neoplasms/etiology ; Breast Neoplasms/genetics ; Case-Control Studies ; Denmark ; Environmental Pollutants/adverse effects ; Environmental Pollutants/metabolism ; Estrogens/metabolism ; Female ; Fluorocarbons/adverse effects ; Fluorocarbons/blood ; Genetic Predisposition to Disease ; Genotype ; Greenland ; Humans ; Middle Aged ; Polymorphism, Genetic ; Prospective Studies ; Risk Factors ; Xenobiotics/metabolism
Chemical Substances	Environmental Pollutants ; Estrogens ; Fluorocarbons ; Xenobiotics
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205699-9
ISSN	1096-0953 ; 0013-9351
ISSN (online)	1096-0953
ISSN	0013-9351
DOI	10.1016/j.envres.2017.01.020
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