Hormonal abnormalities in first-degree relatives of women with polycystic ovary syndrome (PCOS)

PCOS: Inflammation and Infection

Growing evidence supports the concept that PCOS is associated with increased oxidative stress and systemic inflammation. When compared to healthy control subjects, women with PCOS have increased markers of lipid peroxidation, elevated levels of C-reactive protein, inflammatory cytokines, as well as higher concentrations of blood lymphocytes and monocytes.[68,69] However, the cause/causes of these alterations has/have not yet been identified. This suggests a new hypothesis that chronic infections may be involved in the aetiology of PCOS; such chronic infections may induce inflammation and oxidative stress, which in turn may contribute to insulin resistance, ovarian dysfunction and other alterations characteristic of PCOS. In support of this concept, there is evidence that PCOS is associated with a greater risk of exposure to intracellular pathogens capable of inducing long-term inflammation including Chlamydia pneumonia and Chlamydia trachomatis.[70] A correlation between Chlamydia pneumonia and insulin resistance has also been observed.[71] Furthermore, Chlamydia pneumonia infection in mice resulted in increased ovarian size and a greater number of antral follicles.[71]

Coxsackievirus B3 infection affects metal-binding/transporting proteins and trace elements in the pancreas in mice.

Frisk P, Tallkvist J, Gadhasson IL, Blomberg J, Friman G, Ilbäck NG.

Research in Metal Biology, Rudbeck Laboratory, Uppsala University, Sweden. peter.frisk@kemi.uu.se
Abstract

OBJECTIVE: The trigger of juvenile diabetes has been suggested to be an interaction between a virus and trace elements, where enteroviruses, including coxsackievirus B3 (CVB3), have been discussed as potential initiators. The aim of this study was to investigate the effects in the pancreas on gene expressions of metallothionein 1 (MT1), divalent metal transporter 1 (DMT1), and zinc transporter 5 (ZnT-5) and concomitant changes in iron (Fe), copper (Cu), and zinc (Zn) in serum and pancreas of Balb/c mice on days 3, 6, and 9 of CVB3 infection.

METHODS: Trace elements were measured through inductively coupled plasma-mass spectrometry, and CVB3, MT1, DMT1, and ZnT-5 were measured by reverse transcription-polymerase chain reaction.

RESULTS: Virus was found in the pancreas on all days, with a peak on day 3. Infection tended to increase Fe in both serum and the pancreas. The Cu/Zn ratio in the pancreas increased early in the infection because of a great decrease in Zn. In serum, the Cu/Zn ratio was not increased until day 9 of the disease. In the pancreas, MT1 decreased, whereas DMT1 tended to increase on day 6, and ZnT-5 increased progressively during the course of the disease.

CONCLUSIONS: Virus-induced changes in trace elements, MT1, DMT1, and ZnT-5 in the pancreas may reflect early stages of the development of pancreatitis and prestages of diabetic disease.

Elemental Analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-Containing Phagosomes Indicates Pathogen-Induced Microenvironments within the Host Cell’s Endosomal System1
Dirk Wagner2,*,†, Jörg Maser2,‡, Barry Lai‡, Zhonghou Cai‡, Clifton E. Barry, III§, Kerstin Höner zu Bentrup5,¶, David G. Russell¶ and Luiz E. Bermudez3,*
* Kuzell Institute for Arthritis and Infectious Diseases, San Francisco, CA 94115; † Department of Internal Medizin II Infectious Diseases, University of Freiburg, Freiburg, Germany; ‡ Experimental Facilities Division, Argonne National Laboratory, Argonne, IL 60439; § Tuberculosis Research Section, Laboratory of Host Defenses, National Institutes of Health, Rockville, MD 20852; and ¶ Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853

Mycobacterium avium and Mycobacterium tuberculosis are human pathogens that infect and replicate within macrophages. Both organisms live in phagosomes that fail to fuse with lysosomes and have adapted their lifestyle to accommodate the changing environment within the endosomal system. Among the many environmental factors that could influence expression of bacterial genes are the concentrations of single elements within the phagosomes. We used a novel hard x-ray microprobe with suboptical spatial resolution to analyze characteristic x-ray fluorescence of 10 single elements inside phagosomes of macrophages infected with M. tuberculosis and M. avium or with avirulent M. smegmatis. The iron concentration decreased over time in phagosomes of macrophages infected with Mycobacterium smegmatis but increased in those infected with pathogenic mycobacteria. Autoradiography of infected macrophages incubated with 59Fe-loaded transferrin demonstrated that the bacteria could acquire iron delivered via the endocytic route, confirming the results obtained in the x-ray microscopy. In addition, the concentrations of chlorine, calcium, potassium, manganese, copper, and zinc were shown to differ between the vacuole of pathogenic mycobacteria and M. smegmatis. Differences in the concentration of several elements between M. avium and M. tuberculosis vacuoles were also observed. Activation of macrophages with recombinant IFN-γ or TNF-α before infection altered the concentrations of elements in the phagosome, which was not observed in cells activated following infection. Siderophore knockout M. tuberculosis vacuoles exhibited retarded acquisition of iron compared with phagosomes with wild-type M. tuberculosis. This is a unique approach to define the environmental conditions within the pathogen-containing compartment.

Results: Median ferritin concentrations were 155.7 ng/ml for men and 111.9 ng/ml for women. After multiple adjustment, the odds ratios (ORs) were substantially higher for type 2 diabetes (OR 3.26, 95% confidence interval 2.36–4.51) and metabolic syndrome [OR 2.80 (95% confidence interval 2.24–3.49)] in the highest ferritin quartile compared with those in the lowest quartile. These associations remained significant after further adjustment for dietary factors, body mass index, inflammatory markers, and adipokines.

Conclusions: Elevated circulating ferritin concentrations were associated with higher risk of type 2 diabetes and metabolic syndrome in middle-aged and elderly Chinese independent of obesity, inflammation, adipokines, and other risk factors. Our data support the crucial role of iron overload for metabolic diseases, even in a country with relatively high prevalence of iron deficiency.

Pathways underlying iron accumulation in human nonalcoholic fatty liver disease

Conclusions: Iron accumulation in NAFLD may result from an impaired iron export due to down-regulation of FP1 and ineffective hepatic iron sensing, as indicated by low HJV expression. TNF-α appears to play a role in exerting these regulatory changes. Increased hepcidin formation in iron-overloaded NAFLD patients, however, results in decreased duodenal FP-1 expression, whereas a reduction in liver FP-1 may perpetuate hepatic iron retention. Phlebotomy offers a safe and efficient therapy for these metabolic disturbances.

Effects of intravenous infusion of lipopolysaccharide on plasma micromineral, magnesium, and cytokine concentrations and serum cortisol concentrations in lactating goats.

* Wang J, * Jiao L, * Ma J, * Wu C, * Wang K, * Wang M.

College of Veterinary Medicine, China Agricultural University, Beijing 100094, People's Republic of China.

Objective-To assess the effects of various doses of lipopolysaccharide (LPS) administered IV on plasma microminerals, magnesium, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 concentrations and serum cortisol concentrations in lactating goats. Animals-6 lactating goats. Procedures-Goats were allotted to 3 LPS-treatment groups: control (0 mug/kg), low LPS (10 mug/kg), and high LPS (50 mug/kg). Rectal temperatures and behaviors of goats were recorded immediately before a 10-minute IV infusion of LPS and at 0.5, 1, 2, 4, 6, 8, and 24 hours after infusion. Blood samples were obtained before IV infusion and at 0.5, 1, 2, 4, 6, 8, and 24 hours after infusion. Plasma zinc, copper, iron, and magnesium concentrations were determined by atomic absorption spectrometry; plasma TNF-alpha and IL-6 concentrations were measured by use of an ELISA; and serum cortisol concentrations were determined by use of a radioimmunoassay. Results-A monophasic fever developed in low-LPS and high-LPS groups. In the low-LPS and high-LPS group, plasma zinc concentrations decreased at 6 hours after infusion; compared with control groups. Plasma iron concentrations were lower at 24 hours after infusion in low-LPS and high-LPS groups than in the control group. Plasma TNF-alpha and IL-6 concentrations were higher in low-LPS and high-LPS groups than in the control group at 1, 2, and 4 hours after infusion. In low-LPS and high-LPS groups, serum cortisol concentrations increased from 0.5 hours onward and peaked at 1 (high-LPS group) and 2 (low-LPS group) hours after infusion. Conclusions and Clinical Relevance-Following IV infusion of LPS, the immune system is activated, which might affect micromineral homeostatic regulation and, subsequently, the metabolic health of lactating goats.

PMID: 17472454 [PubMed - in process]

This article shows that mice get higher doses of copper after an injection of LPS. This article also shows the effect of LPS on zinc levels: normal (MT+/+) mice had their plasma Zn decreased after the administaration of LPS. Abnormal mice who lack metallothionein, MT-null (MT-/-) mice, did not show this decrease of zinc.

View this article in PubMed
Biochem. J. (1996) 314 (793�797) (Printed in Great Britain)

Trace metal, acute phase and metabolic response to endotoxin in metallothionein-null mice
Allan M. ROFE*, Jeffrey C. PHILCOX and Peter COYLE

Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia

Accumulation of hepatic zinc via metallothionein (MT) induction during infection/inflammation is postulated to benefit a range of metabolic processes. The metabolic consequences of two doses of endotoxin (LPS) (1 and 5 mg/kg, intraperitoneally) were examined in normal (MT+/+) and MT-null (MT-/-) mice (all results means�S.E.M., n = 6). At 16 h after 1 mg/kg LPS, hypozincaemia was pronounced in the MT+/+ mice (4.4�0.2 mM), concomitant with a 36% increase in hepatic Zn and a > 10-fold increase in hepatic MT. Plasma Zn (16.6�0.7 mM) and total hepatic Zn were unchanged in MT-/- mice, confirming the importance of MT in altering plasma and hepatic Zn during inflammation. Plasma iron was lower in LPS-treated MT-/- mice, whereas plasma copper increased to a similar extent in both groups of mice. Plasma fibrinogen more than doubled, and was similar in both groups of mice, which questions the importance of MT in acute-phase protein synthesis. Blood and liver glucose concentrations were not significantly different between groups before or after LPS, whereas blood and liver lactate concentrations were significantly lower (31% and 24% respectively) in MT-/- mice after LPS. At 16 h after 5 mg/kg LPS, plasma Zn was decreased even further in MT+/+ mice (2.6�0.3 mM), but remained unchanged in MT-/- mice at concentrations significantly above those in 16 h-fasted MT-/- mice (15.8�0.5 versus 11.3�0.3 mM). Total liver Zn was 17% lower than fasting values in MT-/- mice, in contrast with 32% higher in MT+/+ mice. Synthesis of MT (in MT+/+ mice) and fibrinogen in all mice was not further enhanced by the higher LPS dose. Blood glucose was significantly decreased by 18% in MT+/+ mice and by 38% in MT-/- mice after 5 mg/kg LPS. There was a marked 44% decrease in liver glucose in MT-/- mice; that in MT+/+ mice was unchanged from fasting levels, implying a deficit in hepatic gluconeogenesis in LPS-treated MT-/- mice. In the absence of any indication of major hepatotoxicity, the results of this study indicate that energy production, and not acute-phase protein synthesis, may be most influenced by Zn supply during endotoxaemia, suggesting that MT has a role in maintaining hepatic and blood glucose in this metabolic setting.