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      Imbalance in the Blood Concentrations of Selected Steroids in Pre-pubertal Gilts Depending on the Time of Exposure to Low Doses of Zearalenone

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          Abstract

          Zearalenone (ZEN) is a mycotoxin that not only binds to estrogen receptors, but also interacts with steroidogenic enzymes and acts as an endocrine disruptor. The aim of this study was to verify the hypothesis that low doses, minimal anticipated biological effect level (MABEL), no-observed-adverse-effect level (NOAEL) and lowest-adverse-effect level (LOAEL), of ZEN administered orally for 42 days can induce changes in the peripheral blood concentrations of selected steroid hormones (estradiol, progesterone and testosterone) in pre-pubertal gilts. The experiment was performed on 60 clinically healthy gilts with average BW of 14.5 ± 2 kg, divided into three experimental groups and a control group. Group ZEN5 animals were orally administered ZEN at 5 μg ZEN/kg BW, group ZEN10 — at 10 μg ZEN/kg BW, group ZEN15 — at 15 μg ZEN/kg BW, whereas group C received a placebo. Five gilts from every group were euthanized on analytical dates 1, 2 and 3 (days 7, 14 and 42 of the experiment). Qualitative and quantitative changes in the biotransformation of low ZEN doses were observed. These processes were least pronounced in group ZEN5 (MABEL dose) where ZEN metabolites were not detected on the first analytical date, and where β-ZEL was the predominant metabolite on successive dates. The above was accompanied by an increase in the concentration of estradiol (E 2) which, together with “free ZEN”, probably suppressed progesterone (P 4) and testosterone (T) levels.

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          Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences.

          This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.
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            Zearalenone as an endocrine disruptor in humans.

            Zearalenone (ZEA), a fungal mycotoxin, is present in a wide range of human foods. Many animal studies have found ZEA to possess a disruptive effect on the hormonal balance, mainly due to its similarity to naturally-occurring estrogens. With increasing consciousness of the adverse effects of endocrine disruptors on human health, it is becoming more important to monitor ZEA concentrations in food and identify its potential effects on human health. Based on a review of recent studies on animal models and molecular pathways in which ZEA is reported to have an influence on humans, we postulate that ZEA might act as an endocrine disruptor in humans in a similar way to animals. Moreover, its endocrine-disrupting effect might be also a causative factor in carcinogenesis. This review article summarizes the latest knowledge about the influence of ZEA on the human hormonal balance.
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              Risks for animal health related to the presence of zearalenone and its modified forms in feed

              Abstract Zearalenone (ZEN), a mycotoxin primarily produced by Fusarium fungi, occurs predominantly in cereal grains. The European Commission asked EFSA for a scientific opinion on the risk to animal health related to ZEN and its modified forms in feed. Modified forms of ZEN occurring in feed include phase I metabolites α‐zearalenol (α‐ZEL), β‐zearalenol (β‐ZEL), α‐zearalanol (α‐ZAL), β‐zearalanol (β‐ZAL), zearalanone (ZAN) and phase II conjugates. ZEN has oestrogenic activity and the oestrogenic activity of the modified forms of ZEN differs considerably. For ZEN, the EFSA Panel on Contaminants in the Food Chain (CONTAM) established no observed adverse effect levels (NOAELs) for pig (piglets and gilts), poultry (chicken and fattening turkeys), sheep and fish (extrapolated from carp) and lowest observed effect level (LOAEL) for dogs. No reference points could be established for cattle, ducks, goats, horses, rabbits, mink and cats. For modified forms, no reference points could be established for any animal species and relative potency factors previously established from rodents by the CONTAM Panel in 2016 were used. The dietary exposure was estimated on 17,706 analytical results with high proportions of left‐censored data (ZEN about 60%, ZAN about 70%, others close to 100%). Samples for ZEN were collected between 2001 and 2015 in 25 different European countries, whereas samples for the modified forms were collected mostly between 2013 and 2015 from three Member States. Based on exposure estimates, the risk of adverse health effects of feed containing ZEN was considered extremely low for poultry and low for sheep, dog, pig and fish. The same conclusions also apply to the sum of ZEN and its modified forms.
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                Author and article information

                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                25 September 2019
                October 2019
                : 11
                : 10
                : 561
                Affiliations
                [1 ]Department of Veterinary Prevention and Feed Hygiene, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13/29, 10-718 Olsztyn, Poland; anna.rykaczewska@ 123456uwm.edu.pl (A.R.); michal.dabrowski@ 123456uwm.edu.pl (M.D.); gajecki@ 123456uwm.edu.pl (M.T.G.); lukaszz@ 123456uwm.edu.pl (Ł.Z.)
                [2 ]Dairy Industry Innovation Institute Ltd., 11-700 Mrągowo, Poland; ewa.onyszek@ 123456iipm.pl (E.O.); andrzej.babuchowski@ 123456iipm.pl (A.B.)
                [3 ]Microbiology Laboratory, Non-Public Health Care Centre, ul. Limanowskiego 31A, 10-342 Olsztyn, Poland; kasiacieplinska@ 123456gmail.com
                [4 ]Independent Public Health Care Centre of the Ministry of the Interior and Administration, and the Warmia and Mazury Oncology Centre in Olsztyn, Wojska Polskiego 37, 10-228 Olsztyn, Poland; lisieska@ 123456wp.pl
                [5 ]Department of Discrete Mathematics and Theoretical Computer Science, Faculty of Mathematics and Computer Science, University of Warmia and Mazury in Olsztyn, Słoneczna 34, 10-710 Olsztyn, Poland; bulma@ 123456uwm.edu.pl
                Author notes
                [* ]Correspondence: mgaja@ 123456uwm.edu.pl
                Article
                toxins-11-00561
                10.3390/toxins11100561
                6832454
                31557818
                7621048b-6417-42b8-977a-b0ae0ff35f2d
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 August 2019
                : 22 September 2019
                Categories
                Article

                Molecular medicine
                zearalenone,low doses,steroid hormones,biotransformation,pre-pubertal gilts
                Molecular medicine
                zearalenone, low doses, steroid hormones, biotransformation, pre-pubertal gilts

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