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Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads

Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compou...

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Autores principales: Zafeiri, Aikaterini, Fowler, Paul A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089997/
http://dx.doi.org/10.1210/jendso/bvab048.998
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author Zafeiri, Aikaterini
Fowler, Paul A
author_facet Zafeiri, Aikaterini
Fowler, Paul A
author_sort Zafeiri, Aikaterini
collection PubMed
description Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compounds. The liver is the primary site of contact with EDs in the fetus. Exposure of the fetal gonads can also alter reproductive function with potential intergenerational effects. We aimed to characterise the metabolic capability of these fetal organs. RNA sequencing was performed in 80 second trimester human fetal livers and 48 fetal gonads (balanced for fetal age and fetal sex). Samples were collected from elective terminations of normal pregnancies (liver 11-19 weeks, FeGo study: REC 04/S0802/21, and gonads 6-17 weeks, as previously described(1). RNA was extracted and Illumina NextSeq was used to produce 76 bp single end (liver) or paired end 2x50 bp (gonads) sequencing reads. Reads were quality controlled, aligned to the human reference genome and quantified at gene regions. Statistical analyses involved an ANOVA model of two-way interactions between fetal sex and fetal age. All organs expressed phase I and II metabolising enzymes and drug transporters involved in the pharmacokinetic and pharmacodynamic pathways of over-the-counter analgesics. The human fetal liver expressed ABCC2, ABCC3, ABCC4 and ABCG2 receptors at similar levels between males and females. Expression of cytochrome p450 enzymes CYP2A6, CYP2C8, CYP2C9, CYP2E1, CYP3A4 involved in metabolism of the analgesics paracetamol and ibuprofen, all increased with gestational age in the liver. Expression of GSTM1, GSTP1, GSTT1, SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1, UGT2B4, UGT2B7 and UGT2B15 metabolising enzymes also increased during gestation, while fetal hepatic GSTP1 expression showed a significant 2-way interaction between both sex and age. Fetal gonads expressed ABCC4 and ABCG2 transporters, with transcript levels demonstrating significant sex-specific and gestational age differences. Fewer analgesic metabolising enzymes were expressed in the gonads than the fetal liver, including CYP2E1, GSTP1 and SULT1A1, all significantly altered by gestation and fetal sex. Our results reveal expression of major analgesics metabolic and transport components within the human fetal liver, ovaries and testes between gestation weeks 7-19. Significant sex alterations in transcript levels also suggest sexually dimorphic metabolic activity of these organs during fetal life. In conclusion, analgesics can be transported into fetal liver and gonad cells and metabolised into bioactive forms, posing toxicity risks for the developing fetus.1. Lecluze E, Rolland AD, Filis P, et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum Reprod. 2020;35(5):1099-1119.
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spelling pubmed-80899972021-05-06 Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads Zafeiri, Aikaterini Fowler, Paul A J Endocr Soc Endocrine Disruption Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compounds. The liver is the primary site of contact with EDs in the fetus. Exposure of the fetal gonads can also alter reproductive function with potential intergenerational effects. We aimed to characterise the metabolic capability of these fetal organs. RNA sequencing was performed in 80 second trimester human fetal livers and 48 fetal gonads (balanced for fetal age and fetal sex). Samples were collected from elective terminations of normal pregnancies (liver 11-19 weeks, FeGo study: REC 04/S0802/21, and gonads 6-17 weeks, as previously described(1). RNA was extracted and Illumina NextSeq was used to produce 76 bp single end (liver) or paired end 2x50 bp (gonads) sequencing reads. Reads were quality controlled, aligned to the human reference genome and quantified at gene regions. Statistical analyses involved an ANOVA model of two-way interactions between fetal sex and fetal age. All organs expressed phase I and II metabolising enzymes and drug transporters involved in the pharmacokinetic and pharmacodynamic pathways of over-the-counter analgesics. The human fetal liver expressed ABCC2, ABCC3, ABCC4 and ABCG2 receptors at similar levels between males and females. Expression of cytochrome p450 enzymes CYP2A6, CYP2C8, CYP2C9, CYP2E1, CYP3A4 involved in metabolism of the analgesics paracetamol and ibuprofen, all increased with gestational age in the liver. Expression of GSTM1, GSTP1, GSTT1, SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1, UGT2B4, UGT2B7 and UGT2B15 metabolising enzymes also increased during gestation, while fetal hepatic GSTP1 expression showed a significant 2-way interaction between both sex and age. Fetal gonads expressed ABCC4 and ABCG2 transporters, with transcript levels demonstrating significant sex-specific and gestational age differences. Fewer analgesic metabolising enzymes were expressed in the gonads than the fetal liver, including CYP2E1, GSTP1 and SULT1A1, all significantly altered by gestation and fetal sex. Our results reveal expression of major analgesics metabolic and transport components within the human fetal liver, ovaries and testes between gestation weeks 7-19. Significant sex alterations in transcript levels also suggest sexually dimorphic metabolic activity of these organs during fetal life. In conclusion, analgesics can be transported into fetal liver and gonad cells and metabolised into bioactive forms, posing toxicity risks for the developing fetus.1. Lecluze E, Rolland AD, Filis P, et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum Reprod. 2020;35(5):1099-1119. Oxford University Press 2021-05-03 /pmc/articles/PMC8089997/ http://dx.doi.org/10.1210/jendso/bvab048.998 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Endocrine Disruption
Zafeiri, Aikaterini
Fowler, Paul A
Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title_full Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title_fullStr Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title_full_unstemmed Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title_short Expression Patterns of Analgesic Metabolising Machinery in 1(st) and 2(nd) Trimester Human Fetal Liver and Gonads
title_sort expression patterns of analgesic metabolising machinery in 1(st) and 2(nd) trimester human fetal liver and gonads
topic Endocrine Disruption
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089997/
http://dx.doi.org/10.1210/jendso/bvab048.998
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