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Fetal programming
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Katherine E. Pelch, Jana L. Allison, Susan C. Nagel
Normal sexual differentiation of the male reproductive tract is androgen dependent. Exposure to antiandrogens during sexual differentiation produces malformations of the reproductive tract in humans and rodents. For example, the fungicide vinclozolin is an antiandrogen. Developmental exposure to vinclozolin during sexual differentiation in rats resulted in reduced anogenital distance, retained nipples, cleft phallus with hypospadias, cryptorchidism, a vaginal pouch, epididymal granulomas, and small-to-absent sex accessory glands (176).
Pesticides and Chronic Diseases
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
On the other hand, growing progress has been made in the recognition of epigenetic modifications in human chronic diseases, particularly cancer. Cancer is now considered as an epigenetic disease, the same as a genetic disease. There is tremendous evidence on the contribution of epigenetic events in the initiation, promotion, and progression of different types of cancers, mainly through silencing of tumor suppressor genes and/or activation of proto-oncogenes. These modifications have allocated such a fundamental role in cancer development that epigenetic therapy of cancer is rapidly growing in medical sciences.1124 In addition, epigenetic changes currently have been a powerful tool for studying the carcinogenesis mechanisms of occupational and environmental exposures.1125 The first note on pesticide-induced carcinogenesis through epigenetic mechanisms was from a study carried out by Maslansky and colleagues in 1981. They reported hepatocarcinogenesis of organochlorine pesticides with no genotoxic effects in hepatocytes and suspected to epigenetic modifications disrupting intracellular communications.1126 Later, reports presented about epigenetic actions of vinclozolin, a fungicide known to be an environmental endocrine disruptor, in association with adult-onset diseases, particularly tumor development.1127 Pesticides were introduced as carcinogens acting through epigenetic or nongenotoxic mechanisms.752
Environmental Androgens and Antiandrogens: An Expanding Chemical Universe
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
L. Earl Gray, Vickie Wilson, Tammy Stoker, Christy Lambright, Johnathan Furr, Nigel Noriega, Phillip Hartig, Mary Cardon, Mitch Rosen, Gerald Ankley, Andrew Hotchkiss, Edward F. Orlando, Louis J. Guillette, William R. Kelce
Vinclozolin, procymidone, iprodione, and chlozolinate are dicarboximide fungicides. Vinclozolin and procymidone are AR antagonists with equivalent potency, while iprodione and chlozolinate do not appear to be antiandrogenic in vivo.37 Of the antiandrogenic EDCs, the mechanism of action of vinclozolin is the most thoroughly characterized. Vinclozolin metabolites, M1 and M2 competitively inhibit the binding of androgens to AR of several species from different vertebrate classes.7,38 M1 and M2 also inhibit DHT-induced transcriptional activity in cells transfected with the human AR. Kelce et al.39 subsequently demonstrated that vinclozolin treatment altered the expression of androgen-dependent genes in vivo in an antiandrogenic manner, similar to the antiandrogenic drug flutamide. In contrast, neither vinclozolin nor its metabolites display affinity for the estrogen receptor, although they do have weak affinity for the progesterone receptor.40 Furthermore, vinclozolin, M1, and M2 do not inhibit 5α-reductase activity, the enzyme required for the conversion of testosterone (T) to the more active androgen DHT.7
In vitro phase I metabolism of vinclozolin by human liver microsomes
Published in Xenobiotica, 2019
Marycarmen Cruz-Hurtado, Ma de Lourdes López-González, Victor Mondragón, Adolfo Sierra-Santoyo
Pesticides are a heterogeneous group of chemicals to control and repel pests in different fields. Vinclozolin (Vin) is a nonsystemic dicarboximide fungicide used to prevent rotting of several fruits, vegetable, ornamental plants and turf grass (Szeto et al., 1989; US EPA, 2000). Human exposure to Vin can occur via ingestion of contaminated produce food and drink or from occupational use.
Molecular interactions of vinclozolin metabolites with human estrogen receptors 1GWR-α and 1QKM and androgen receptor 2AM9-β: Implication for endocrine disruption
Published in Toxicology Mechanisms and Methods, 2020
Haroon Habib, Md Rafi Haider, Shikha Sharma, Shahzad Ahmad, Sadaf Dabeer, Mohammad Shahar Yar, Sheikh Raisuddin
Vinclozolin (VCZ) (CAS 50471-44-8; 3-(3,5-dichlorophenyl)−5-methyl-5-vinyloxazolidine-2,4-dione); (Figure 1) is a dicarboximide fungicide used to treat fungal influx in fruits and vegetables (Rasmusssen et al. 2003; Spanoghe et al. 2010; Cho et al. 2014). VCZ finds its way into the human body by consumption of food treated with it (Balinova et al. 2006; Zhang et al. 2016). VCZ is reported to be found in human food chain due to the consumption of contaminated food which leads to ill effects on human health (Harvey and Johnson 2002; Wickerham et al. 2012; Csaba 2017). VCZ is one of the potential endocrine disrupting chemicals (EDCs), as it directly interferes with the hormonal system (Kavlock and Cummings 2005; Buckley et al. 2006). Several effects including epigenetic changes have been reported due to the exposure to VCZ (Durkin et al. 1995; Nilsson et al. 2018). VCZ exposure is reported to cause reproductive disorders, cancers and obesity (Kavlock and Cummings 2005; Csaba 2017). It inhibits androgen and estrogen receptor functioning by proactively binding to active protein site and is implicated in some diseases (Gray et al. 2006; Skinner 2014; Nilsson et al. 2018). Several studies have reported the interaction of VCZ with nuclear receptors such as estrogen receptors (ERs) androgen receptors (ARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and lysophosphatidic acid receptor (LPAR) and affecting many physiological functions (Grün et al. 2006; Helsen and Claessens 2014; Sharma et al. 2018; Tachachartvanich et al. 2018). Estrogen and testosterone regulate the functions of reproductive system and also play an important role in functioning of immune system, cardiovascular system and nervous system in humans (Vrtačnik et al. 2014; Ribas et al. 2016; Hart-Unger et al. 2017). ER mediates the action of estrogen hormone by its direct interaction with DNA which eventually results in the expression of target genes (Kiyama and Wada-Kiyama 2015; Fuentes and Silveyra 2017; Burns et al. 2018). Interaction of EDCs with both ER and AR is amongst the important mechanisms of action of EDCs. Study of interaction of ER and AR with xenobiotics offers valuable insight into the mechanism of their potential of disrupting endocrine system. It is facilitated by extensive protein data bank (PDB) of ER and AR of almost all the species (Shimamura et al. 2002; McRobb et al. 2014; Hala 2017).