09.12.3 1 ENDOCRINE DISRUPTIONS ZOO3603C Two Critical Books Of Endocrine Disruptions  1962 Rachel Carson, “Silent Spring” warned that pesticides were destroying wildlife.  1996 Theo Colborn et al., “Our Stolen Future” brought world-wide attention to scientific discoveries about endocrine disruption and the fact that common contaminants can interfere with the natural signals controlling development of the fetus. Environmental Endocrine Disruptors  Endocrine disruptors: Any exogenous substances that can alters the function of endogenous endocrine system.  Endocrine disruptors = Endocrine Disrupting Chemicals or compounds (EDCs) Irreversible alterations Environmental Endocrine Disruptors  EDCs can alter endocrine function by a variety of different mechanisms: 1. Mimicking the steroid hormones or thyroid hormones by binding to endogenous receptors either as agonists or antagonists. 2. Altering the synthesis and breakdown of natural hormones. 3. Modifying the production and functioning of hormone receptors. http://www3.interscience.wiley.com:8100/legacy/college/boyer/0471661791/cutting_edge/endocrine_disrupting/endocrine_disrupting.htm Source of estrogenic compounds  Drugs: birth control pills, diethylstilbestrol  Pesticides: DDT, DDE  Industrial compounds: Polychlorinated biphenyls (PCBs), Bisphenol-A (BPA)  Plant-derived estrogens: Phytoestrogens Structures of some endocrine disruptors Estrogenic Compounds 09.12.3 2 Structures of some endocrine disruptors Phytoestrogens soy and red clover Structures of some endocrine disruptors Their structures are similar to endogenous hormones. Effects of exposure to diethylstilbestrol on the female reproductive system In the US, an estimated 5-10 million persons were exposed to DES during 1941-1971. Persistent vaginal cornification in mice  1962 Takasugi et al., Science 138:438-9 Persistent vaginal cornification induced in mice by brief postnatal treatment with estrogen is not prevented by later ovariectomy, adrenalectomy, or hypophysectomy. The vaginal epithelium of the persistently estrous mouse appears to represent an altered cell population which does not require estrogen for its constant keratinization.  1971 Herbst et al., N Engl J Med 284: 878–81  DES therapy started during the first trimester of pregnancy by mothers of 7 of 8 girls and young women ages 14 to 22 diagnosed with adenocarcinoma of the vagina. Irreversible alterations Out of endogenous physiological regulation Abnormalities of the reproductive tract in perinatal DES-exposed mice  Ovary-independent cervicovaginal keratinization  Adenosis  Uterine hypoplasia  Epithelial metaplasia  Oviductal tumors  Polyovular follicles (PF)  Polyfollicular ovaries HoxA gene expression in female reproductive tract Upper vagina and cervix By half of oviduct By uterus/oviduct boundary starts to diminish at middle By uterus/oviduct boundary Ma et al., Dev Biol 197, 141–154 (1998) 09.12.3 3 In situ hybridization of a Hoxa10 probe shows that DES exposure represses Hoxa10  Perinatal DES administration induces endometriosis in uterus.  Prenatal DES administration repressed Hoxa10 expression. Ma et al., Dev Biol 197, 141–154 (1998) Misregulation of Müllerian duct morphogenesis by DES A summary of DES-regulated genes in the mouse Ma Trends Endocrinol Metab 20:357-63 (2009) Effects of estrogen implants on different strains of mice Effects of estrogen implants on different strains of mice Different strains of mice  Different strains of mice show different sensitivity to different signals at the different end point, although this example is reversible alteration in adult testis.  CD-1 strain is more sensitive to the induction of polyovular (multioocytic) follicles in DES-exposed ovary than B6 strain. 09.12.3 4 Bisphenol A causes meiotic defects in maturing oocytes +BPA Control Chromosomes (red) lined up at the center of the spindle at the 1st meiotic metaphase Chromosomes (red) align on the spindle randomly. Polyovular (multioocytic) follicles ? Ability of a mixture of estrogenic compounds at low concentrations Trans-activation assay (reporter gene assay) Mixture could induce the trans-activation more than the single compound. Testicular dysgenesis and declining sperm counts  Sperm counts: Men born before 1959 > after 1970  Testicular cancers: 2.5 higher in 2000 than 1970.  Testicular dysgenesis syndrome: Disorganized testis development, testicular germ cell tumors and low sperm levels; can be induced by phthalate derivative.  Phthalates are ubiquitous in industrialized society.  Plastic, cosmetics and almost every industrial product. Trans-generational effects of vinclozolin  Testicular dysgenesis syndrome also could be induced by dioxins, nonylphenol, bisphenol A and etc.  Pesticide – Infertility  Methoxychlor  Vinclozolin Control Grandfather’s mother had been injected with vinclozolin Trans-generational alteration Methylation? Endocrine disruptions in wildlife Temperature-dependent sex determination in three reptile species09.12.3 5 Temperature-Dependent Sex Determination in American Alligator Turtles Alligators Effect of EDCs on sex determination in the red-eared slider turtle Willingham and Crews, Gen Comp Endo 1999. Demasculinization of frogs by low amounts of atrazine Concern over atrazine’s apparent ability to disrupt sex hormones in both wildlife and humans has resulted in bans on the use of this herbicide by France, Germany, Italy, Norway, Sweden and Switzerland. Xenopus, ZZ: ZW type Control Male Atrazine-exposed ZZ Possible chain of causation leading to feminization of male frogs and the decline of frog populations In regions where atrazine has been used to control weed populations Possible chain of causation leading to feminization of male frogs and the decline of frog populations Retinoid-induced malformations  Retinoic acid (RA) is important in forming the anterior-posterior axis of mammalian embryo.  About 160,000 women took the pills of RA in 1980s.  In 1985, of their 59 fetuses, 33 were born with abnormality. 09.12.3 6 Retinoid-induced malformations  Human took RA by the pills.  How animals can receive RA in the wild?  Derivative of Methoprene (juvenile hormone). Retinoid-induced malformations Polymelia,