Effects of isoflavones on breast tissue and the thyroid hormone system in humans: a comprehensive safety evaluation.

Isoflavones are secondary plant constituents of certain foods and feeds such as soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations are marketed as food supplements and so-called dietary food for special medical purposes to alleviate health complaints of peri- and postmenopausal women. Based on the bioactivity of isoflavones, especially their hormonal properties, there is an ongoing discussion regarding their potential adverse effects on human health. This review evaluates and summarises the evidence from interventional and observational studies addressing potential unintended effects of isoflavones on the female breast in healthy women as well as in breast cancer patients and on the thyroid hormone system. In addition, evidence from animal and in vitro studies considered relevant in this context was taken into account along with their strengths and limitations. Key factors influencing the biological effects of isoflavones, e.g., bioavailability, plasma and tissue concentrations, metabolism, temporality (pre- vs. postmenopausal women), and duration of isoflavone exposure, were also addressed. Final conclusions on the safety of isoflavones are guided by the aim of precautionary consumer protection.

Contamination of organic nutrient sources with potentially toxic elements, antibiotics and pathogen microorganisms in relation to P fertilizer potential and treatment options for the production of sustainable fertilizers: A review.

Organic nutrient sources such as farmyard manure, sewage sludge, their biogas digestates or other animal by-products can be valuable fertilizers delivering organic matter to the soil. Currently, especially phosphorus (P) is in the focus of research since it is an essential plant nutrient with finite resources, estimated to last only for some more decades. Efficient utilization of organic P sources in agriculture will help to preserve P resources and thereby has the potential to close nutrient cycles and prevent unwanted P-losses to the environment, one of the major causes for eutrophication of water bodies. Unfortunately, organic P sources usually contain also various detrimental substances, such as potentially toxic elements or organic contaminants like pharmaceuticals as well as pathogenic microorganisms. Additionally, the utilization of some of these substrates such as sewage sludge or animal by-products is legally limited in agriculture because of the potential risk to contaminate sites with potentially toxic elements and organic contaminants. Thus, to close nutrient cycles it is important to develop solutions for the responsible use of organic nutrient sources. The aim of this review is to give an overview of the contamination of the most important organic nutrient sources with potentially toxic elements, antibiotics (as one important organic contaminant) and pathogenic microorganisms. Changes in manure and sewage sludge management as well as the increasing trend to use such substrates in biogas plants will be discussed with respect to potential risks posed to soils and water bodies. Some examples for abatement options by which contamination can be reduced to produce P fertilizers with high amounts of plant available P forms are presented.

Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B).

The objective of this study was to synthesize and evaluate a novel fluorine-18 labeled deuterium substituted analogue of rasagiline (9, [(18)F]fluororasagiline-D2) as a potential PET radioligand for studies of monoamine oxidase B (MAO-B). The precursor compound (6) and reference standard (7) were synthesized in multi-step syntheses. Radiolabeling of 9 was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulfamidate group. The incorporation radiochemical yield from fluorine-18 fluoride was higher than 30%, the radiochemical purity was >99% and the specific radioactivity was >160GBq/µmol at the time of administration. In vitro compound 7 inhibited the MAO-B activity with an IC50 of 173.0±13.6nM. The MAO-A activity was inhibited with an IC50 of 9.9±1.1µM. The fluorine-18 version 9 was characterized in the cynomolgus monkey brain where a high brain uptake was found (275% SUV at 4min). There was a higher uptake in the striatum and thalamus compared to the cortex and cerebellum. A pronounced blocking effect (50% decrease) was observed in the specific brain regions after administration of l-deprenyl (0.5mg/kg) 30min prior to the administration of 9. Radiometabolite studies demonstrated 40% of unchanged radioligand at 90min post injection. An efficient radiolabeling of 9 was successfully established and in the monkey brain 9 binds to MAO-B rich regions and its binding is blocked by the selective MAO-B compound l-deprenyl. The radioligand 9 is a potential candidate for human PET studies.

Estrogenic and genotoxic potential of equol and two hydroxylated metabolites of Daidzein in cultured human Ishikawa cells.

The soy isoflavone daidzein (DAI) is known to undergo metabolism to equol (EQO) and to 3'-hydroxy-DAI (3'-HO-DAI) and 6-hydroxy-DAI (6-HO-DAI) in humans. In order to better understand the implications of soy diets for human health, the hormonal and genotoxic activities of these DAI metabolites were studied in cultured human endometrial carcinoma cells. When the estrogenicity was tested by cell-free binding to recombinant human estrogen receptor (ER) alpha and beta as well as by the induction of enzyme activity and gene expression of alkaline phosphatase (ALP) in Ishikawa cells, the ranking order was EQO>DAI>3'-HO-DAI>6-HO-DAI. All compounds had a higher affinity to ERbeta than to ERalpha. No significant anti-estrogenic effects of the DAI metabolites were observed in the cells at non-cytotoxic concentrations. The in vitro genotoxicity was assessed by analyzing effects on cell cycle distribution and cell morphology as well as the induction of micronuclei (MN). EQO caused a slight increase in G1 and decrease in S phase of the cell cycle, and slightly but significantly induced kinetochore-positive as well as kinetochore-negative MN and an elevated proportion of abnormal mitotic spindles. 3'-HO-DAI, but not 6-HO-DAI, induced kinetochore-negative MN. The observation that major human metabolites of DAI exhibit estrogenic and genotoxic potential may be of relevance for the safety evaluation of diets containing soy isoflavones.

[Retino-hypothalamic pathways in vertebrates]. / Retino-hypothalamische Verbindungen bei Wirbeltieren.

Forty years ago Hollwich (1948) introduced the conception of an "energetic portion of the visual pathway". Contributions to this conception of a direct connection of the retina with the hypothalamus accumulated since then and summarized here in tabular form give rise to the following conclusions: In fish the main hypothalamic termination of retinofugal axons is the nucleus hypothalamicus opticus. It may pass for the suprachiasmatic nucleus of fishes. In amphibians retino-hypothalamic fibres project to the area praeoptica. In reptiles retinofugal fibres innervate hypothalamic neuronal populations called either Nucleus suprachiasmaticus or Nucleus praeopticus. In birds retinohypothalamic axons project to a circumscribed anterior hypothalamic area termed "suprachiasmatic nucleus" by some authors. In mammals at last the main part of the retinohypothalamic tract terminates in the suprachiasmatic nuclei, especially favouring their caudal and ventrolateral parts. The interneuronal connections are axo-dendritic synapses of the Gray Types-I and II. Connections of retinal neurons, especially with suprachiasmatic hypothalamic nuclei or their homologues, are by now well established facts. They represent relatively constant and phylogenically stable components of the centripetal retinal projection. These projections are probably in all, certainly in most of the vertebrates bilateral. Some former but also newer methods of research (Stumpf and Sar, 1975) also depicted optic fibers which terminate in hypothalamic sites apart from the nucleus suprachiasmaticus and the area hypothalamica anterior (Conrad and Stumpf, 1975). A review of the literature on the existence of nerve fibers directly connecting the retina with the hypothalamus is tabulated.