Immunohistochemical evaluation of apoptosis and proliferation in the mucous membrane of selected uterine regions in pre-pubertal bitches exposed to low doses of zearalenone

Abstract

Mycotoxins are toxic secondary metabolites produced by fungi. Those biologically active compounds occur naturally and they include zearalenone (ZEN), a mycotoxin that contaminates plant material, including the ingredients used in the production of commercial dog food. The influence of monotonic, low-dose and long-term exposure to ZEN on pre-pubertal bitches has not been fully explored to date. This paper describes a 42-day experiment performed on clinically healthy female dogs aged approximately 70 days, with estimated body weight of 8 kg. The animals were randomly divided into two experimental groups (EI and EII) and a control group (C) of 10 animals each. Group EI received 50 μg ZEN/kg (of body weight) per os, group EII received 75 μg ZEN/kg BW per os, and the control group was administered placebo. The bitches were ovariohysterectomized at the end of the experiment (at around 112 days of age), and selected sections of the uterine wall were subjected to immunohistochemical analyses (TUNEL and PCNA). A shift towards higher apoptotic (AI) and proliferative index (PI) was observed, in particular in group EI. Higher AI and PI values were noted in the epithelium of all uterine regions analysed and in the uterine glands in the uterine horn proximal to the body of the uterus.

The Genotoxicity of Caecal Water in Gilts Exposed to Low Doses of Zearalenone

“…During the synthesis of these catechol metabolites, ZEN activity becomes similar to that of endogenous estrogens E 2 and E 1 . These promiscuous steroids [ 40 ] and steroid-like substances are associated with the risk of bowel cancer [ 41 ], breast cancer [ 35 ], uterine cancer [ 9 ], and malignant changes in other estrogen-sensitive organs [ 21 ]. There is evidence to indicate that E 2 /E 1 catechol metabolites are weak genotoxins that contribute to malignant transformations by producing quinones that generate DNA adducts [ 42 ].…”

“…The above is confirmed by the hormesis paradigm [ 6 , 7 ]. Doses below the lowest observed adverse effect level (LOAEL) values [ 8 , 9 ] that produce subclinical symptoms of disease are referred to as no observed adverse effect levels (NOAEL) doses [ 10 ]. The lowest measurable dose that enters positive interactions with the host’s body in various stages of life is known as the minimal anticipated biological effect level (MABEL) dose [ 11 ].…”

Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

“…ZEA is structurally similar to estrogen and competes with estradiol for binding to estrogen receptors, and stimulates estrogenic activity, which may cause several physiological alterations in the reproductive tract (56). In vitro study has indicated that ZEA may regulate metabolic processes, including cell proliferation, differentiation and apoptosis (57). The regulatory role of ZEA in endometriosis has also been demonstrated (58).…”

Activity of Zearalenone in the Porcine Intestinal Tract

“…The health (toxicological) effects of low mycotoxin doses became apparent in the last decade. They are associated with hormesis [ 36 , 37 ], a biological phenomenon whereby exposure to doses below the NOAEL [ 38 ] induces disease without clinical symptoms (subclinical state) [ 15 , 39 ] or delivers beneficial effects for the host in various stages of life [ 40 ]. The dose-response relationship was put into question by the low-dose hypothesis, in particular with regard to hormonally active chemicals [ 41 ] such as ZEN and its metabolites.…”