| 1. |
- de Paula, Helena Korres, et al.
(författare)
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KEAP1 polymorphisms and neurodevelopmental outcomes in children with exposure to prenatal MeHg from the Seychelles Child Development Study Nutrition Cohort 2
- 2023
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Ingår i: NeuroToxicology. - 1872-9711. ; 99, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Humans differ in the metabolism of the neurotoxicant methyl mercury (MeHg). This variation may be partially due to variation in genes encoding the transcription factor Nuclear factor E2-related factor 2 (NRF2) and its negative regulator Kelch-like ECH-Associated Protein 1 (KEAP1), which regulate glutathione and related transporter and antioxidant proteins that play a role in the metabolism and neurotoxicity of MeHg.AIM: To elucidate a potential risk from genetic variation in NFE2L2 (encoding NRF2) and KEAP1 toward prenatal mercury exposure and child neurodevelopmental outcomes at 20 months and 7 years of age in a population with variable prenatal exposure to MeHg from maternal fish consumption.MATERIAL AND METHODS: Nutrition Cohort 2 is a mother-child cohort in the Republic of Seychelles. Children were genotyped for NFE2L2 (rs2364723, rs13001694) and KEAP1 (rs8113472, rs9676881) polymorphisms (N = 1,285 after removing siblings). Total mercury (Hg) was measured in cord blood as a biomarker for prenatal MeHg exposure. Child neurodevelopmental outcomes included the Bayley Scales of Infant Development II administered at 20 months of age, and outcomes across multiple neurodevelopmental domains from 14 tests administered in children and 3 instruments completed by parents when children were 7 years of age.RESULTS: The mean cord blood MeHg concentration was 34 (95% CI 11, 75) µg/L. None of the four polymorphisms had a significant association (p<0.05) with either cord MeHg or neurodevelopmental test results at 20 months. There were no significant associations between either NFE2L2 polymorphism and any developmental test scores. At 7 years, children carrying KEAP1 rs8113472 CA showed significantly worse performance on psychomotor function than children with the CC variant (finger tapping, dominant hand: β -1.19, SE 0.34; finger tapping, non-dominant hand: β -0.92, SE 0.31) and worse social communication (SCQ Total: β 0.65, SE 0.27). Children carrying rs8113472 AA, versus children with CC, showed significantly better performance on social communication (SRS Total: β -8.88, SE 3.60). Children carrying KEAP1 rs9676881 AG, versus children with GG, showed significantly worse performance on psychomotor function (trailmaking A time: β 8.66, SE 3.37) and cognition (KBIT Matrices: β -0.96, SE 0.36).CONCLUSION: No associations between NFE2L2 and KEAP1 polymorphisms and MeHg concentration were identified. However, at 7 years, KEAP1 polymorphisms were associated with differences in neurodevelopmental outcomes in children from a population with high fish intake.
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| 2. |
- Julander, Anneli, et al.
(författare)
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Nickel penetration into stratum corneum in FLG null carriers—A human experimental study
- 2022
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 87:2, s. 154-161
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Tidskriftsartikel (refereegranskat)abstract
- Background: The filaggrin gene (FLG) plays a role in skin diseases, with the skin barrier function being impaired in FLG null carriers. The role of FLG status in relation to nickel penetration into the skin remains unclear. Objectives: To elucidate the association between FLG status and nickel penetration into stratum corneum (SC) in individuals without self-reported history of nickel allergy. Methods: Forty participants (23 FLG wt and 17 FLG null) were exposed to a nickel solution (80 μg/cm2) which was applied onto 2 × 2 cm on their left forearm. After 4 h, the area was tape-stripped with 10 consecutive tapes. Nickel in each tape was quantified using inductively coupled plasma mass spectrometry. Results: The average recovered nickel dose was 35%–48%. A tendency towards lower recovery was seen in FLG null carriers compared to FLG wt carriers, and lower recovery in those with history of skin and/or respiratory symptoms compared to those without such history. This was however not statistically significant. Conclusion: FLG null carriers had less nickel recovered by tape strips compared with FLG wt carriers and, compared with individuals without a history of skin and/or respiratory symptoms, indicating higher nickel penetration into SC for FLG null carriers, but further studies are needed.
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| 3. |
- Liljedahl, Emelie Rietz, et al.
(författare)
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Filaggrin polymorphisms and the uptake of chemicals through the skin—a human experimental study
- 2021
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Ingår i: Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 129:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals. OBJECTIVE: The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype. METHOD: We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects’ urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis. RESULTS: Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20–22 repeats) and high FLG CNV (23–24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (AUCð0–40hÞ ) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by AUCð0–40hÞ ) for pyrimethanil than wt carriers with low and high CNV, respectively. CONCLUSION: We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310.
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| 4. |
- Liljedahl, Emelie Rietz, et al.
(författare)
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Inflammation-related proteins in blood after dermal exposure to some common chemicals depend on the skin barrier gene filaggrin - a human experimental study
- 2024
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Ingår i: Environmental Toxicology and Pharmacology. - 1382-6689 .- 1872-7077. ; 105
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Tidskriftsartikel (refereegranskat)abstract
- Filaggrin (FLG), a skin barrier protein, is associated with higher dermal uptake of some chemicals in carriers of loss-of-function (null) mutations. This study investigates FLG mutations and systemic effects following dermal exposure to chemicals. Individuals (n = 23 FLG null, n = 31 FLG wt) were simultaneously exposed to pyrimethanil, pyrene, oxybenzone, and nickel ions for 4 h. Pre- and post-exposure, 25-hydroxyvitamin D3 (25(OH)D3, LC-MS/MS) and 92 inflammation-related proteins (proximity-extension assay) were measured. FLG null carriers exhibited significantly higher 25(OH)D3 concentrations than wt carriers, both pre- and post-exposure. Eleven proteins differed in abundance post- vs pre-exposure among FLG null carriers, and 22 proteins among wt carriers (three proteins overlapped). Twelve proteins showed median differences (post- vs pre-exposure) between FLG null and wt carriers. Overall, FLG null carriers showed an increase, while FLG wt carriers showed a decrease in inflammation-related proteins. These findings suggest FLG-dependent differences in susceptibility to systemic effects following simultaneous dermal chemical exposure.
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