Filis, P., Nagrath, N., Fraser, M., Hay, D. C., Iredale, J. P., O'Shaughnessy, P. and Fowler, P. A. (2015) Maternal smoking dysregulates protein expression in second trimester human fetal livers in a sex-specific manner. Journal of Clinical Endocrinology and Metabolism, 100(6), E861-E870. (doi: 10.1210/jc.2014-3941) (PMID:25803269) (PMCID:PMC4533306)
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Abstract
Context: Maternal smoking during pregnancy has adverse effects on the offspring (eg, increased likelihood of metabolic syndrome and infertility), which may involve alterations in fetal liver function. Objective: Our aim was to analyze, for the first time, the human fetal liver proteome to identify pathways affected by maternal smoking. Design: Fetal liver proteins extracted from elective second trimester pregnancy terminations (12–16 weeks of gestation) were divided in four balanced groups based on sex and maternal smoking. Setting and Participants: Livers were collected from 24 morphologically normal fetuses undergoing termination for nonmedical reasons and analyzed at the Universities of Aberdeen and Glasgow. Main Outcome Measures: Protein extracts were resolved by 2D-PAGE and analyzed with SameSpots software. Ingenuity pathway analysis was used to investigate likely roles of dysregulated proteins identified by tandem liquid chromatography/mass spectroscopy. Results: Significant expression differences between one or more groups (fetal sex and/or maternal smoking) were found in 22 protein spots. Maternal smoking affected proteins with roles in post-translational protein processing and secretion (ERP29, PDIA3), stress responses and detoxification (HSP90AA1, HSBP1, ALDH7A1, CAT), and homeostasis (FTL1, ECHS1, GLUD1, AFP, SDHA). Although proteins involved in necrosis and cancer development were affected in both sexes, pathways affecting cellular homeostasis, inflammation, proliferation, and apoptosis were affected in males and pathways affecting glucose metabolism were affected in females. Conclusions: The fetal liver exhibits marked sex differences at the protein level, and these are disturbed by maternal smoking. The foundations for smoke-induced post-natal diseases are likely to be due to sex-specific effects on diverse pathways. The liver is essential for detoxification and homeostasis by metabolizing and/or assisting in the excretion of a wide range of xenotoxicants including alcohol, drugs, and tobacco smoke constituents. In the human the fetal liver is active and because 70% of its blood supply is directly from the fetomaternal interface, it is directly exposed to potentially harmful agents from the maternal circulation. Tobacco smoke contains a mixture of ∼5000 chemicals and the human fetal liver responds to maternal smoking by up-regulating phase I and phase II enzyme transcripts (1). Strikingly, the human fetal liver also expresses transcripts and proteins associated with altering steroid hormone function/activity in the mother and fetus. These include CYP19A1 (2), CYP3A7 (2, 3), and SULT enzymes (2, 4). The fetal liver is the main hematopoietic organ during the second trimester in humans (5) and also secrets high levels of α-fetoprotein (AFP), sex-hormone binding globulin (6), IGF-I, and IGF-II (7). It is clear, therefore, that the human fetal liver functions in the development and protection of the fetus and in the regulation of steroid hormone levels/actions during pregnancy. Maternal smoking is associated with diverse negative outcomes for the health of the neonate [including reduced birth weight, premature delivery, and stillbirth (8, 9)] and predisposition of the offspring to long-term health risks [including metabolic syndrome (10, 11), reduced fertility (12, 13), and psychosomatic problems (15)]. Approximately 30% of women continue to smoke once pregnant (16) and it remains one of the most important modifiable risk factors during pregnancy. Maternal smoking restricts the fetal oxygen supply and increases carbon monoxide burden to the conceptus but also disrupts fetal development through other mechanisms; previous studies from this group have identified some of these mechanisms such as endocrine signaling (1, 17) but a greater understanding of how maternal smoking links to disease in the offspring is required. Given the importance of the fetal liver to human fetal development and its susceptibility to maternal smoking we have, for the first time, used a proteomics approach to identify proteins and pathways that are dysregulated in the human fetal liver by maternal smoking.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | O'Shaughnessy, Professor Peter |
| Authors: | Filis, P., Nagrath, N., Fraser, M., Hay, D. C., Iredale, J. P., O'Shaughnessy, P., and Fowler, P. A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | Journal of Clinical Endocrinology and Metabolism |
| Publisher: | The Endocrine Society |
| ISSN: | 0021-972X |
| ISSN (Online): | 1945-7197 |
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