Transcriptional analysis of endocrine disruption using zebrafish and massively parallel sequencing

  1. Gary Hardiman1,2
  1. Department of Medicine, University of California San Diego, 9500 Gilman Drive 0605, La Jolla, California 92093-0605, USA
    1CSRC and BIMRC, San Diego State University, 5500 Campanile Drive, San Diego, California 92182-7720, USA
    2Department of Medicine, Medical University of South Carolina, 135 Cannon Street, Suite 303 MSC 835, Charleston, South Carolina 29425, USA
  1. Correspondence should be addressed to M E Baker or G Hardiman; Emails: mebaker{at} or hardiman{at}
  1. Figure 1

    Adrenal and sex steroids. Estradiol (E2) is the canonical female sex steroid. However, E2 is more than a reproductive steroid: E2 has important actions in heart, brain, liver, bone in females and males (Heldring et al. 2007, Sugiyama et al. 2010, Gao & Dahlman-Wright 2011, Baker 2013). Moreover, E2 has an important role in prostate physiology (Weihua et al. 2002, Prins et al. 2011). Thus, EDC binding to the ER can affect reproductive physiology in males as well as non-reproductive physiology in males and females. Testosterone and 5α-dihydrotestosterone (DHT) are two male androgens (Sharifi & Auchus 2012), which also are important hormones for females. In humans, progesterone is important for successful implantation of the fertilized egg (Graham & Clarke 1997, Smith 2007). Progesterone antagonists, such as RU486, can interfere with implantation and prevent pregnancy. However, as with E2, progesterone has actions in males and in tissues that are not directly involved in reproduction. Cortisol is involved in response to stress, metabolism of carbohydrates and lipids, bone turnover, lung maturation, and homeostasis of the immune, cardiovascular, and CNSs (Sapolsky et al. 2000, Tomlinson et al. 2004, Zhou & Cidlowski 2005, Odermatt & Gumy 2008, McEwen 2012). Although these actions are mediated primarily by the glucocorticoid receptor (GR); in some cells, cortisol is a transcriptional activator of the mineralocorticoid receptor (MR). Aldosterone regulates electrolyte homeostasis by controlling transport of sodium and potassium in kidney and gut through transcriptional activation of the MR (Hawkins et al. 2012, Martinerie et al. 2013). However, MR also is important in other organs such as heart and brain, in which the MR may be activated by aldosterone or cortisol (Tomlinson et al. 2004, Funder 2009).

  2. Figure 2

    Structures of xenoestrogens and xenoandrogens. (A) Xenoestrogens (Kuiper et al. 1998, Sonnenschein & Soto 1998, Diamanti-Kandarakis et al. 2009). A key property of xenoestrogens is the presence of one or more phenolic groups in a structure that mimics either A or the A and D rings of E2. Examples are diethylstilbestrol, (DES), a synthetic estrogen, 4-nonylphenol (NP) and bisphenol A (BPA), which are used in plastics, 4-methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (MBP), a metabolite of BPA (Yamaguchi et al. 2005, Baker & Chandsawangbhuwana 2012), which has over 100-fold higher affinity for the ER than BPA and zearalenone, which is a toxic estrogenic metabolite synthesized by some fungi (Katzenellenbogen et al. 1979). However, chemicals without hydroxyl substituents also can disrupt estrogen physiology. Examples are DDT (Sonnenschein & Soto 1998), a pesticide, and polychlorinated hydroxybiphenyls (PCBs), which are used in transformers and capacitors (Korach et al. 1988, Kuiper et al. 1998). (B) Xenoandrogens (Kelce et al. 1998, Sonnenschein & Soto 1998, Diamanti-Kandarakis et al. 2009, Luccio-Camelo & Prins 2011). A variety of structures, which do not have much in common with either DHT or T can bind the AR. Vinclozolin, a fungicide, is an antiadrogen, as are p,p′-DDE, a metabolite of p,p′-DDT, the insecticide fenitrothion (Tamura et al. 2001) and the herbicide linuron (Lambright et al. 2000). Hydroxy-flutamide is an anti-androgen used in treating prostate cancer.

  3. Figure 3

    Schema for transcriptome sequencing and analysis.

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