ABSTRACT
OBJECTIVE: Weight gain is a common side effect of antidepressive treatment, causing distress among patients and caretakers as it can lead to treatment discontinuation and complications such as diabetes type II and cardiovascular disease. Vortioxetine is one of the newer antidepressants and the pharmacodynamics differ from the selective serotonin reuptake inhibitors. It is marketed as being weight neutral; however, there is little evidence as to why. In recent years, there has been an increased focus on the faecal microbiota and its impact on body weight and mental and physical health. In the current work, we examine the effect of vortioxetine on weight gain and faecal microbiota composition. METHODS: Forty male C57BL/6NTac mice were primed for 8 weeks with a high-fat diet (Hfd) or control diet (Cd), followed by a 4-week period on the same diet and additional +/- vortioxetine 10 mg/kg/daily. RESULTS: Vortioxetine reduced Hfd-induced weight gain (Hfd + V: 8.2%, Hfd - V: 12.7%; p = 0.0374) but did not affect weight gain of the control group (Cd + V: 7.54%, Cd - V: 7.56%; p = 0.4944). Significant differences in faecal microbiota were observed in mice who received vortioxetine. CONCLUSION: Vortioxetine caused significant changes to the faecal microbiota composition and appeared to limit Hfd-induced weight gain.
ABSTRACT
Obesity has become a global health challenge also affecting reproductive health. In pregnant women, obesity increases the risk of complications such as preterm birth, macrosomia, gestational diabetes, and preeclampsia. Moreover, obesity is associated with long-term adverse effects for the offspring, including increased risk of cardiovascular and metabolic diseases and neurodevelopmental difficulties. The underlying mechanisms are far from understood, but placental function is essential for pregnancy outcome. Transporter proteins P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are important for trans-placental transport of endogenous substances like lipids and cortisol, a key hormone in tissue maturation. They also hold a protective function protecting the fetus from xenobiotics (e.g. pharmaceuticals). Animal studies suggest that maternal nutritional status can affect expression of placental transporters, but little is known about the effect on the human placenta, especially in early pregnancy. Here, we investigated if overweight and obesity in pregnant women altered mRNA expression of ABCB1 encoding P-gp or ABCG2 encoding BCRP in first trimester human placenta. With informed consent, 75 first trimester placental samples were obtained from women voluntarily seeking surgical abortion (< gestational week 12) (approval no.: 20060063). Villous samples (average gestational age 9.35 weeks) were used for qPCR analysis. For a subset (n = 38), additional villi were snap-frozen for protein analysis. Maternal BMI was defined at the time of termination of pregnancy. Compared to women with BMI 18.5-24.9 kg/m2 (n = 34), ABCB1 mRNA expression was significantly increased in placenta samples from women classified as overweight (BMI 25-29.9 kg/m2, n = 18) (p = 0.040) and women classified as obese (BMI ≥ 30 kg/m2, n = 23) (p = 0.003). Albeit P-gp expression did not show statistically significant difference between groups, the effect of increasing BMI was the same in male and female pregnancies. To investigate if the P-gp increase was compensated, we determined the expression of ABCG2 which was unaffected by maternal obesity (p = 0.291). Maternal BMI affects ABCB1 but not ABCG2 mRNA expression in first trimester human placenta. Further studies of early placental function are needed to understand how the expression of placental transport proteins is regulated by maternal factors such as nutritional status and determine the potential consequences for placental-fetal interaction.
Subject(s)
Placenta , Premature Birth , Animals , Female , Pregnancy , Humans , Male , Infant, Newborn , Infant , Placenta/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Pregnancy Trimester, First , Overweight/metabolism , Pregnant Women , Neoplasm Proteins/genetics , Premature Birth/metabolism , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Obesity/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Carrier Proteins/metabolism , RNA, Messenger/metabolismABSTRACT
STUDY QUESTION: Does maternal smoking in early pregnancy affect metallothionein 1 and 2 (MT1 and MT2) mRNA and protein expression in first trimester placenta or embryonic/fetal liver? SUMMARY ANSWER: In the first trimester, MT protein expression is seen only in liver, where smoking is associated with a significantly reduced expression. WHAT IS KNOWN ALREADY: Zinc homeostasis is altered by smoking. Smoking induces MT in the blood of smokers properly as a result of the cadmium binding capacities of MT. In term placenta MT is present and smoking induces gene and protein expression (MT2 in particular), but the MT presence and response to smoking have never been examined in first trimester placenta or embryonic/fetal tissues. STUDY DESIGN, SIZE, DURATION: Cross sectional study where the presence of MT mRNA and protein was examined at the time of the abortion. The material was collected with informed consent after surgical intervention and frozen immediately. For protein expression analysis, liver tissue originating from smoking exposed n = 10 and unexposed n = 12 pregnancies was used. For mRNA expression analyses, placental tissue originating from smokers n = 19 and non-smokers n = 23 and fetal liver tissue from smoking exposed n = 16 and smoking unexposed pregnancies n = 13, respectively, were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Tissues were obtained from women who voluntarily and legally chose to terminate their pregnancy between gestational week 6 and 12. Western blot was used to determine the protein expression of MT, and real-time PCR was used to quantify the mRNA expression of MT2A and eight MT1 genes alongside the expression of key placental zinc transporters: zinc transporter protein-1 (ZNT1), Zrt-, Irt-related protein-8 and -14 (ZIP8 and ZIP14). MAIN RESULTS AND THE ROLE OF CHANCE: A significant reduction in the protein expression of MT1/2 in liver tissue (P = 0.023) was found by western blot using antibodies detecting both MT forms. Overall, a similar tendency was observed on the mRNA level although not statistically significant. Protein expression was not present in placenta, but the mRNA regulation suggested a down regulation of MT as well. A suggested mechanism based on the known role of MT in zinc homeostasis could be that the findings reflect reduced levels of easily accessible zinc in the blood of pregnant smokers and hence a reduced MT response in smoking exposed fetal/embryonic tissues. LIMITATIONS AND REASONS FOR CAUTION: Smoking was based on self-reports; however, our previous studies have shown high consistency regarding cotinine residues and smoking status. Passive smoking could interfere but was found mainly among smokers. The number of fetuses was limited, and other factors such as medication and alcohol might affect the findings. Information on alcohol was not consistently obtained, and we cannot exclude that it was more readily obtained from non-users. In the study, alcohol consumption was reported by a limited number (less than 1 out of 5) of women but with more smokers consuming alcohol. However, the alcohol consumption reported was typically limited to one or few times low doses. The interaction between alcohol and smoking is discussed in the paper. Notably we would have liked to measure zinc status to test our hypothesis, but maternal blood samples were not available. WIDER IMPLICATIONS OF THE FINDINGS: Zinc deficiency-in particular severe zinc deficiency-can affect pregnancy outcome and growth. Our findings indicate that zinc homeostasis is also affected in early pregnancy of smokers, and we know from pilot studies that even among women who want to keep their babies, the zinc status is low. Our findings support that zinc supplements should be considered in particular to women who smoke. STUDY FUNDING/COMPETING INTEREST(S): We thank the Department of Biomedicine for providing laboratory facilities and laboratory technicians and the Lundbeck Foundation and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Legat for financial support. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.
Subject(s)
Liver/enzymology , Maternal Exposure , Metallothionein/metabolism , Smoking/adverse effects , Zinc/blood , Abortion, Induced , Cross-Sectional Studies , Denmark , Dietary Supplements , Female , Gene Expression Profiling , Gene Expression Regulation, Developmental , Humans , Liver/embryology , Placenta/metabolism , Pregnancy , Pregnancy Trimester, FirstABSTRACT
Prenatal exposure to maternal cigarette smoking increases the risk of intrauterine growth retardation, adverse pregnancy outcomes, and diseases later in life. Exposure can result in postnatal global and gene-specific DNA methylation changes, with the latter well documented for the CYP1A1 and AHRR genes involved in the detoxification of xenobiotic substances. This study assessed the impact of exposure to maternal smoking on first trimester fetal CYP1A1 and AHRR mRNA expression and DNA methylation for CpG-sites displaying maternal smoking during pregnancy-mediated methylation changes at birth. The analyses included first trimester (6-12 weeks) placentas (N=39) and livers (N=43). For AHRR, exposure to maternal smoking was associated with increased DNA methylation in the placentas of female fetuses; mRNA expression, however, was unchanged. While exposure to maternal smoking was not associated with AHRR DNA methylation changes in fetal livers; mRNA expression was increased. For CYP1A1, exposure to maternal smoking was not associated with fetal DNA methylation changes whereas mRNA expression increased in placentas and male fetal livers. These results show that first trimester exposure to maternal smoking is associated with CYP1A1 and AHRR DNA methylation and mRNA expression changes. However, the results also indicate that maternal smoking during pregnancy-mediated postnatal CYP1A1 and AHRR DNA methylation changes are not imprinted during the first trimester.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Cigarette Smoking/genetics , Cytochrome P-450 CYP1A1/genetics , DNA Methylation , Pregnancy Trimester, First/genetics , Repressor Proteins/genetics , Female , Humans , Liver/metabolism , Male , Maternal Exposure , Maternal-Fetal Exchange , Placenta/metabolism , Pregnancy , RNA, Messenger/metabolismABSTRACT
AIMS: Maternal cigarette smoking during pregnancy increases the risk of negative health consequences for the exposed child. Epigenetic mechanisms constitute a likely link between the prenatal exposure to maternal cigarette smoking and the increased risk in later life for diverse pathologies. Maternal smoking induces gene-specific DNA methylation alterations as well as global DNA hypermethylation in the term placentas and hypomethylation in the cord blood. Early pregnancy represents a developmental time where the fetal epigenome is remodeled and accordingly can be expected to be highly prone to exposures with an epigenetic impact. We have assessed the influence of maternal cigarette smoking during the first trimester for fetal global DNA methylation. METHODS AND RESULTS: We analyzed the human fetal intestines and livers as well as the placentas from the first trimester pregnancies. Global DNA methylation levels were quantified with ELISA using a methylcytosine antibody as well as with the bisulfite pyrosequencing of surrogate markers for global methylation status, LINE-1, and AluYb8. We identified gender-specific differences in global DNA methylation levels, but no significant DNA methylation changes in exposure responses to the first trimester maternal cigarette smoking. CONCLUSIONS: Acknowledging that only examining subsets of global DNA methylation markers and fetal sample availability represents possible limitations for the analyses, our presented results indicate that the first trimester maternal cigarette smoking is not manifested in immediate aberrations of fetal global DNA methylation.