Academic journal article Environmental Health Perspectives

Transfer and Metabolism of the Xenoestrogen Zearalenone in Human Perfused Placenta

Academic journal article Environmental Health Perspectives

Transfer and Metabolism of the Xenoestrogen Zearalenone in Human Perfused Placenta

Article excerpt


Zearalenone (ZEN) is a fungal toxin (mycotoxin) produced by Fusarium species and is regularly found in cereal-based food and feed in various countries (Maragos 2010; EFSA 2011; Mally et al. 2016). Other sources, such as legume-based food and vegetable oils, were also reported (Schollenberger et al. 2007; Maragos 2010; EFSA 2011). Because this mycotoxin possesses potent estrogenic activity, it is often referred to as xeno- or mycoestrogen (Bennett and Klich 2003; Kowalska et al. 2016; Warth et al. 2018). Humans are frequently exposed to low doses, either directly by ingestion of contaminated food or indirectly by the consumption of livestock that were fed with contaminated chow (Kowalska et al. 2016).

The most prevalent phase I metabolites are [alpha]- and [beta]-zearalenol ([alpha]- and [beta]-ZEL) and [alpha]- and [beta]-zearalanol ([alpha]- and [beta]-ZAL) (Miles et al. 1996; Pfeiffer et al. 2011), whereas zearalanone (ZAN) is a metabolite of [alpha]-ZAL (Migdalof et al. 1983). The favorably formed metabolite is highly dependent on the species [reviewed in Zinedine et al. (2007)]. Detoxification occurs via phase II metabolism by sulfation and glucuronidation (Migdalof et al. 1983; Miles et al. 1996; Pfeiffer et al. 2011).

The human metabolism of ZEN has been characterized in cell models (Pfeiffer et al. 2010, 2011) as well as in vivo in human intervention studies (Mirocha et al. 1981; Warth et al. 2013). It is mainly metabolized via phase I metabolism to [alpha]-ZEL and to a minor extent to [beta]-ZEL and is thereafter glucuronidated. ZEL metabolites were also shown in vitro using Caco-2 cells to conjugate to sulfate metabolites (Pfeiffer et al. 2011). In line with this, Huuskonen et al. (2015) unraveled human placental phase I metabolism of ZEN to [alpha]-ZEL and to a minor extent to [beta]-ZEL in chorion carcinoma JEG-3 cells and human term placental subcellular fractions.

ZEN is often referred to as an endocrine-disrupting chemical (EDC) (Kowalska et al. 2016). According to the European Commission, EDCs are "substances that alter the functions of the hormonal system and consequently cause adverse effects" (EC 2018). ZEN and several of its metabolites can bind to estrogen receptors and resemble, therefore, with different potency, the estrogenic properties of endogenous estrogens. [alpha]-ZEL was demonstrated to be the most potent structure, being about 70 times more potent than the parent toxin ZEN (Frizzell et al. 2011), followed by [alpha]-ZAL and ZEN (Arukwe et al. 1999; Malekinejad et al. 2005; Frizzell et al. 2011; Tatay et al. 2017). Phase II metabolism (glucuronidation and sulfation) reduced estrogenicity in cell models (Jard et al. 2010; Frizzell et al. 2015).

Environmental exposure to molecules mimicking endogenous estrogens, so-called xenoestrogens, may result in various adverse effects in different human organs, including the reproductive tract and the nervous system (Singleton and Khan 2003). Such adverse effects have been reported frequently in animal studies [reviewed in Xu et al. (2017)] but human data are difficult to generate due to the complexity of the endocrine system and the diversity of xenoestrogens, which usually appear at low doses in various mixtures. Moreover, there is growing evidence that exposure to xenoestrogens at early developmental stages can be related to chronic diseases later in life, such as breast cancer and the development of other tumors (Palmlund 1996; Fernandez and Russo 2010; Fucic et al. 2012).

Consequently, the investigation of the in utero and early life exposure to xenoestrogens is of high priority. Different approaches have been developed to study the permeability of the human placental barrier [reviewed in Muoth et al. (2016)]. Among these, the dually perfused ex vivo placental perfusion model provides highly predictive, human-relevant data on the transfer and metabolism of compounds due to the use of intact human placental tissue and dynamic exposure conditions (Panigel et al. …

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