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Caporale, N., Leemans, M., Birgersson, L., Germain, P.-L., Cheroni, C., Borbely, G., . . . Testa, G. (2022). From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures. Science, 375(6582), Article ID 735.
Open this publication in new window or tab >>From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures
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2022 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 375, no 6582, article id 735Article in journal (Refereed) Published
Abstract [en]

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS)American Association for the Advancement of Science (AAAS), 2022
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-470672 (URN)10.1126/science.abe8244 (DOI)000758142600037 ()35175820 (PubMedID)
Funder
EU, European Research Council, DISEASEAVATARS 616441Swedish Research Council FormasEU, Horizon 2020, 825759
Available from: 2022-03-29 Created: 2022-03-29 Last updated: 2024-01-15Bibliographically approved
Smirnova, A., Mentor, A., Ranefall, P., Bornehag, C.-G., Brunström, B., Mattsson, A. & Jönsson, M. (2021). Increased apoptosis, reduced Wnt/β-catenin signaling, and altered tail development in zebrafish embryos exposed to a human-relevant chemical mixture. Chemosphere, 264(1), Article ID 128467.
Open this publication in new window or tab >>Increased apoptosis, reduced Wnt/β-catenin signaling, and altered tail development in zebrafish embryos exposed to a human-relevant chemical mixture
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2021 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 264, no 1, article id 128467Article in journal (Refereed) Published
Abstract [en]

A wide variety of anthropogenic chemicals is detected in humans and wildlife and the health effects of various chemical exposures are not well understood. Early life stages are generally the most susceptible to chemical disruption and developmental exposure can cause disease in adulthood, but the mechanistic understanding of such effects is poor. Within the EU project EDC-MixRisk, a chemical mixture (Mixture G) was identified in the Swedish pregnancy cohort SELMA by the inverse association between levels in women at around gestational week ten with birth weight of their children. This mixture was composed of mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mono-isononyl phthalate, triclosan, perfluorohexane sulfonate, perfluorooctanoic acid, and perfluorooctane sulfonate. In a series of experimental studies, we characterized effects of Mixture G on early development in zebrafish models. Here, we studied apoptosis and Wnt/β-catenin signaling which are two evolutionarily conserved signaling pathways of crucial importance during development. We determined effects on apoptosis by measuring TUNEL staining, caspase-3 activity, and acridine orange staining in wildtype zebrafish embryos, while Wnt/β-catenin signaling was assayed using a transgenic line expressing an EGFP reporter at β-catenin-regulated promoters. We found that Mixture G increased apoptosis, suppressed Wnt/β-catenin signaling in the caudal fin, and altered the shape of the caudal fin at water concentrations only 20–100 times higher than the geometric mean serum concentration in the human cohort. These findings call for awareness that pollutant mixtures like mixture G may interfere with a variety of developmental processes, possibly resulting in adverse health effects.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Mixtures, Zebrafish, Apoptosis, Wnt/beta-catenin, PFOS
National Category
Environmental Sciences Developmental Biology
Identifiers
urn:nbn:se:uu:diva-409016 (URN)10.1016/j.chemosphere.2020.128467 (DOI)000599817400057 ()33032226 (PubMedID)
Funder
EU, Horizon 2020, 634880Swedish Institute
Note

Title in thesis list of papers: Increased apoptosis, reduced Wnt/β-catenin signaling, and altered tail development in zebrafish embryos exposed to a chemical mixture that has been inversely associated with birth weight in humans

Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2024-01-15Bibliographically approved
Mentor, A., Bornehag, C.-G., Jönsson, M. & Mattsson, A. (2020). A suggested bisphenol A metabolite (MBP) interfered with reproductive organdevelopment in the chicken embryo while a human-relevant mixture ofphthalate monoesters had no such effects. Journal of Toxicology and Environmental Health, 83(2), 66-81
Open this publication in new window or tab >>A suggested bisphenol A metabolite (MBP) interfered with reproductive organdevelopment in the chicken embryo while a human-relevant mixture ofphthalate monoesters had no such effects
2020 (English)In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 83, no 2, p. 66-81Article in journal (Refereed) Published
Abstract [en]

Bisphenol A (BPA) and phthalate diesters are ubiquitous environmental contaminants. While thesecompounds have been reported as reproductive toxicants, their effects may partially be attributedto metabolites. The aim of this study was to examine reproductive organ development in chickenembryos exposed to the BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP;100 μg/g egg) or a human-relevant mixture of 4 phthalate monoesters (85 μg/g egg). The mixturewas designed within the EU project EDC-MixRisk based upon a negative association with anogenitaldistance in boys at 21 months of age in a Swedish pregnancy cohort. Chicken embryoswere exposed in ovo from an initial stage of gonad differentiation (embryonic day 4) anddissected two days prior to anticipated hatching (embryonic day 19). No discernible effectswere noted on reproductive organs in embryos exposed to the mixture. MBP-treated malesexhibited retention of Müllerian ducts and feminization of the left testicle, while MBPadministeredfemales displayed a diminished the left ovary. In the left testicle of MBP-treatedmales, mRNA expression of female-associated genes was upregulated while the testicular markergene SOX9 was downregulated, corroborating a feminizing effect by MBP. Our results demonstratethat MBP, but not the phthalate monoester mixture, disrupts both male and femalereproductive organ development in an avian embryo model.

Place, publisher, year, edition, pages
Taylor & Francis, 2020
Keywords
Chicken embryo, feminization, mixture, phthalates, 4-methyl-2, 4-bis(4-hydroxyphenyl)pent-1-ene (MBP)
National Category
Environmental Sciences Developmental Biology
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-406961 (URN)10.1080/15287394.2020.1728598 (DOI)000514984300001 ()32077375 (PubMedID)
Funder
EU, Horizon 2020, 634880
Available from: 2020-03-17 Created: 2020-03-17 Last updated: 2020-04-17Bibliographically approved
Mentor, A., Wänn, M., Brunström, B., Jönsson, M. & Mattsson, A. (2020). Bisphenol AF and Bisphenol F Induce Similar Feminizing Effects in Chicken Embryo Testis as Bisphenol A. Toxicological Sciences, 178(2), 239-250
Open this publication in new window or tab >>Bisphenol AF and Bisphenol F Induce Similar Feminizing Effects in Chicken Embryo Testis as Bisphenol A
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2020 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 178, no 2, p. 239-250Article in journal (Refereed) Published
Abstract [en]

The plastic component bisphenol A (BPA) impairs reproductive organ development in various experimental animal species. In birds, effects are similar to those caused by other xenoestrogens. Because of its endocrine disrupting activity, BPA is being substituted with other bisphenols in many applications. Using the chicken embryo model, we explored whether the BPA alternatives bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol S (BPS) can induce effects on reproductive organ development similar to those induced by BPA. Embryos were exposed in ovo from embryonic day 4 (E4) to vehicle, BPAF at 2.1, 21, 210, and 520 nmol/g egg, or to BPA, BPF, or BPS at 210 nmol/g egg and were dissected on embryonic day 19. Similar to BPA, BPAF and BPF induced testis feminization, manifested as eg testis-size asymmetry and ovarian-like cortex in the left testis. In the BPS-group, too few males were alive on day 19 to evaluate any effects on testis development. We found no effects by any treatment on ovaries or Mullerian ducts. BPAF and BPS increased the gallbladder-somatic index and BPAF, BPF and BPS caused increased embryo mortality. The overall lowest-observed-adverse-effect level for BPAF was 210 nmol/g egg based on increased mortality, increased gallbladder-somatic index, and various signs of testis feminization. This study demonstrates that the BPA replacements BPAF, BPF, and BPS are embryotoxic and suggests that BPAF is at least as potent as BPA in inducing estrogen-like effects in chicken embryos. Our results support the notion that these bisphenols are not safe alternatives to BPA.

Place, publisher, year, edition, pages
OXFORD ENGLAND: , 2020
Keywords
bisphenols, BPAF, BPF, BPS endocrine disruption, chicken, development, testis
National Category
Environmental Sciences
Identifiers
urn:nbn:se:uu:diva-435410 (URN)10.1093/toxsci/kfaa152 (DOI)000608394200003 ()33010167 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-899
Available from: 2021-02-26 Created: 2021-02-26 Last updated: 2023-10-31Bibliographically approved
Mentor, A., Brunström, B., Mattsson, A. & Jönsson, M. (2020). Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio). Chemosphere, 238, Article ID 124584.
Open this publication in new window or tab >>Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio)
2020 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 238, article id 124584Article in journal (Refereed) Published
Abstract [en]

Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfiuorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3 h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2020
Keywords
Mixtures, Metabolism, Adipogenesis, Zebrafish, Endocrine disrupting chemicals
National Category
Environmental Sciences
Identifiers
urn:nbn:se:uu:diva-398425 (URN)10.1016/j.chemosphere.2019.124584 (DOI)000497885800054 ()31470313 (PubMedID)
Funder
EU, Horizon 2020, 634880
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2020-04-17Bibliographically approved
Gao, K., Tian, J., Wu, Y., Mein, P., Zhang, Z., Jönsson, M. & Brandt, I. (2020). Induction of Cytochrome P4501 Genes by Various Inducers in Rainbow Trout (Oncorhynchus mykiss). Journal of Coastal Research, 37(1), 143-148
Open this publication in new window or tab >>Induction of Cytochrome P4501 Genes by Various Inducers in Rainbow Trout (Oncorhynchus mykiss)
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2020 (English)In: Journal of Coastal Research, ISSN 0749-0208, E-ISSN 1551-5036, Vol. 37, no 1, p. 143-148Article in journal (Refereed) Published
Abstract [en]

Juvenile rainbow trout is widely found in various aquatic systems, such as freshwater, coastal, and marine habitats all over the world. Expression patterns of the cytochrome P4501 (CYP1) genes exposed to various stressors in such fish could be informative and useful in biomonitoring. In the present study, the induction of CYP1 in rainbow trout by indigo, humic acid (HA), and benzo(a)pyrene (BaP) was studied through a 12-hour exposure experiment by using rainbow trout as an experimental object. First, 7-ethoxyresorufin O-deethylase (EROD) activity and CYP1 expression levels in fish exposed to different concentrations of indigo were analyzed. The EROD activities in fish gills were greatly affected by the concentration of indigo (1, 18, 50, and 80 nM). The expression level of CYP1A1 and CYP1A3 in gills was higher compared with CYP1B1 and CYP1Cs. Second, the gill EROD activity and CYP1 mRNA expressions levels were compared when induced by indigo, HA, and BaP at the same concentration (1 nM). Results indicated that rainbow trout were sensitive to all three inducers. Among them, the HA affected CYP1A1 and CYP1A3 most obviously. CYP1A, as an important biomarker, was more sensitive than CYP1B and CYP1C to those inducers. The observed effects of the different CYP1 inducers could provide a useful tool for monitoring of AhR-active pollutants in the aquatic environment.

Place, publisher, year, edition, pages
COASTAL EDUCATION & RESEARCH FOUNDATION, 2020
Keywords
CYP1, indigo, HA, BaP
National Category
Pharmacology and Toxicology Environmental Sciences
Identifiers
urn:nbn:se:uu:diva-435126 (URN)10.2112/JCOASTRES-D-20-00036.1 (DOI)000607009800013 ()
Funder
Swedish Research Council Formas
Available from: 2021-02-22 Created: 2021-02-22 Last updated: 2021-02-22Bibliographically approved
Galus, M., Fraz, S., Gugilla, A., Jönsson, M. & Wilson, J. Y. (2020). Prostaglandins prevent acetaminophen induced embryo toxicity in zebrafish (Danio rerio). Environmental Toxicology and Pharmacology, 80, Article ID 103463.
Open this publication in new window or tab >>Prostaglandins prevent acetaminophen induced embryo toxicity in zebrafish (Danio rerio)
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2020 (English)In: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 80, article id 103463Article in journal (Refereed) Published
Abstract [en]

Previous research in our laboratory showed that acetaminophen (ACE) induced embryonic mortality and abnormalities in zebrafish. Here, we examined the dose response of ACE (0.05-50 mu g L-1 ) in zebrafish embryos. Concentrations as low as 0.1 mu g L-1 significantly increased abnormalities, and all test concentrations significantly increased mortality rates. In mammals, ACE inhibits cyclooxygenase (COX) enzymes to decrease prostaglandin production. Here we report COX activity and expression of the cox-1, cox-2a, and cox-2b genes in zebrafish embryos. COX activity was significantly inhibited by specific mammalian cox-1 (SC-560) and cox-2 (DuP-697) inhibitors in unexposed and ACE-exposed embryos. COX activity declined with development time. Maternal transcripts of all cox genes were found at 1 -h post fertilization and embryonic expression began in gastrulation or early segmentation. Co-exposure of ACE and prostaglandin E2 abolished the ACE-induced effects. This strongly supports that ACE elicits embryo toxicity in zebrafish though the same molecular mechanism of action of their therapeutic effects in mammals.

Place, publisher, year, edition, pages
ELSEVIER, 2020
Keywords
Acetaminophen, Cyclooxygenase, Prostaglandin, Development, Gene expression
National Category
Developmental Biology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-428048 (URN)10.1016/j.etap.2020.103463 (DOI)000583776900022 ()32822849 (PubMedID)
Funder
Swedish Research Council FormasCarl Tryggers foundation
Available from: 2020-12-14 Created: 2020-12-14 Last updated: 2020-12-14Bibliographically approved
Beijer, K., Jönsson, M., Shaik, S., Behrens, D., Brunström, B. & Brandt, I. (2018). Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss). Aquatic Toxicology, 198, 73-81
Open this publication in new window or tab >>Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss)
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2018 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 198, p. 73-81Article in journal (Refereed) Published
Abstract [en]

Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes.

We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo. The advantage of this method is that both induction and inhibition of EROD are performed ex vivo. Among thirteen azoles studied, the five that caused the strongest inhibition of gill EROD activity at a concentration of 5 μM were selected for concentration–response assessment. These compounds (bifonazole, clotrimazole, imazalil, miconazole, and prochloraz) showed IC50 values ranging from 0.1 to 1.5 μM. CYP19 (aromatase) inhibition was measured using microsomes from rainbow trout brains. Concentration-response curves for CYP19 inhibition were determined for letrozole, bifonazole, clotrimazole, imazalil, miconazole and prochloraz, which gave IC50 values ranging from 0.02 to 3.3 μM. It was further found that mixtures of the five most potent azoles reduced both CYP1 and 19 catalytic activity in an additive fashion (IC50 = 0.7 μM and 0.6 μM, in the respective assay). Bifonazole (IC50 = 0.1 μM) is not previously known to inhibit CYP1 activity.

The additive inhibition of CYP1 and CYP19 catalytic activity is an important finding of the present study. We conclude that this additive action of azoles could mediate adverse impacts on CYP regulated physiological functions in environmentally exposed fish.

Keywords
Azole fungicide, EROD activity, cytochrome P450 (CYP), CYP1A, CYP19, aromatase, pharmaceutical, contaminant, chemical, fish, rainbow trout, gill, EROD aktivitet, cytokrom P450 (CYP), CYP1A, CYP19, aromatase, läkemedel, azol, fungicid, kemikalier, förorening, fisk, regnbågslax, gäle
National Category
Other Biological Topics
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-249010 (URN)10.1016/j.aquatox.2018.02.016 (DOI)000430630100008 ()
Funder
Mistra - The Swedish Foundation for Strategic Environmental Research
Available from: 2015-04-15 Created: 2015-04-10 Last updated: 2018-08-07Bibliographically approved
Wincent, E., Kubota, A., Timme-Laragy, A., Jönsson, M. E., Hahn, M. E. & Stegeman, J. J. (2016). Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner. Biochemical Pharmacology, 110, 117-129
Open this publication in new window or tab >>Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner
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2016 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 110, p. 117-129Article in journal (Refereed) Published
Abstract [en]

6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.

Keywords
Aryl hydrocarbon receptor; Cytochrome P4501; 6-Formylindolo[3, 2-b]carbazole; Enzyme inhibition; Zebrafish embryo toxicity; Synergistic receptor activation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-296689 (URN)10.1016/j.bcp.2016.04.012 (DOI)000377738400011 ()27112072 (PubMedID)
Funder
Swedish Research Council Formas, 2011-963 2008-1249EU, European Research Council, 634880
Available from: 2016-06-19 Created: 2016-06-19 Last updated: 2017-11-28Bibliographically approved
Jönsson, M. E., Mattsson, A., Shaik, S. & Brunström, B. (2016). Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos. Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, 179, 125-136
Open this publication in new window or tab >>Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos
2016 (English)In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 179, p. 125-136Article in journal (Refereed) Published
Abstract [en]

The tryptophan derivative formylindolo[3,2-b]carbazole (FICZ) binds with high ligand affinity to the aryl hydrocarbon receptor (AHR) and is readily degraded by AHR-regulated cytochrome P450 family 1 (CYP1) enzymes. Whether in vivo exposure to FICZ can result in toxic effects has not been examined and the main objective of this study was to determine if FICZ is embryotoxic in birds. We examined toxicity and CYP1 mRNA induction of FICZ in embryos from chicken (Gallus domesticus) and Japanese quail (Coturnix japonica) exposed to FICZ (2200 jag kg(-1)) by yolk and air sac injections. FICZ caused liver toxicity, embryo mortality, and CYP1A4 and CYP1A5 induction in both species with similar potency. This is in stark contrast to the very large difference in sensitivity of these species to halogenated AHR agonists. We also exposed chicken embryos to a low dose of FICZ (4 mu g kg(-1)) in combination with a CYP inhibitor, ketoconazole (KCZ). The mixture of FICZ and KCZ was lethal while FICZ alone had no effect at 4 mu g kg(-1). Furthermore, mixed exposure to FICZ and KCZ caused stronger and more long-lasting hepatic CYP1A4 induction than exposure to each compound alone. These findings indicate reduced biotransformation of FICZ by co-treatment with KCZ as a cause for the enhanced effects although additive AHR activation is also possible. To conclude, FICZ is toxic to bird embryos and it seems reasonable that the toxicity by FICZ involves AHR activation. However, the molecular targets and biological events leading to hepatic damage and mortality are unknown.

Keywords
Formylindolo[3, 2-b]carbazole (FICZ), Cytochrome P450 1 (CYP1), Chicken, Japanese quail, Embryo toxicity, Liver necrosis
National Category
Ecology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-274425 (URN)10.1016/j.cbpc.2015.09.014 (DOI)000366873300016 ()26456929 (PubMedID)
Funder
Swedish Research Council Formas, 216-2008-1249Carl Tryggers foundation , CTS 12:227
Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2018-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7664-7562

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