A brief overview of my field, Reproductive Toxicology.

1. Reproductive Toxicology Erin Legacki December 6, 2009 Animal Biology 290

2. What is Reproductive Toxicology? Effects of chemicals on the reproductive and neuroendocrine systems the embryo, fetus, neonate and prepubertal mammal.

3. Modes of Disruption Morphology Disruption Reproductive tract malformation Hermaphrodite Endocrine Disruption Feminization Altered circulating hormones

4. Usual Suspects Dichlorodiphenyltrichloroethane DDT Pesticide BisphenolA BPA Plastics Found in polycarbonate

5. Silent Spring: Classic Examples Rachel Carson – 1962 Chronicled DDT effects on wildlife Bird Focus Bald Eagle California Condor Thinning of egg shells

6. Morphology Disruption Alterations to the reproductive tract In utero Hormone sensitive tissue Hermaphroditic

7. Diethylstilbestrol - DES Synthetic estroegn Developed in 1938 Prescribed to prevent miscarriages/premature births (1938-1971) 5-10 million exposed DES Daughters Reproductive tract malformation Cancer ( breast and cervical)

8. Arctic Problem 1 in 50 female Polar Bears are hermaphrodites High levels of polybrominateddiphenyls Little more then 50% have cubs Of 45 Beluga whales 41% had breast tumors Compromised milk production 1 was hermaphroditic High levels of organochlorinated compounds

9. Amphibians Frogs Atrazine causes hermaphroditic reproductive tracts Feminization Salamanders Endosulfan disrupts pheremones Alters developing glands Global amphibian decline

10. Testicular Dysgensis Syndrome Cryptorchidism Hypospadia Low Sperm Count Testicular germ cell death Cancer 15% of all couples are infertile 20% is male infertility

11. Endocrine Disruption Several modes of disruption Mimic Bisphenol A Block Flutamide Metabolize Dexamethasone

12. Hormone Mimics Similar affinity Activate pathway No regulation Changes in hormone levels

13. Receptor Blockers Bind to receptor Compete with hormone Block feedback Changes in hormone level

14. Hormone metabolism Up-regulation of hepatic and renal clearance Dexamethasone Up-regulates CYP 3A Testosterone to 6β- hydroxytesterone Polybrominateddiphenyl ether (PBDE) Increased hepatic enzyme activity

15. Lake Apopka Alligators Tower Chemical Company Spill – 1980 Mass die off of alligators Decrease in clutch viability Juvenile mortality 20 years later Decrease in testosterone Small phallus size Altered reproductive tract

16. Back to male infertility Decline in male fertility (101 studies in 28 countries) 113 million sperm/ml in 1938 66 million sperm/ml in 1991 1.5% / year decline in the US No clear reason why???

17. Phthalate Esters Anti-androgen compounds Make plastics flexible Children’s toys Medical equipment Enteric coating of pharmaceuticals Malformation of reproductive tissue Multinucleated germ cells Decreased Sperm Count

18. Sertoli Cell Primary support for germ cells Paracrine Anti-Mullerican Hormone Follicle Stimulating Hormone Structural Tight Junctions Immune protection

19. Sertoli Cell + Phthalates In Utero Decreased Anti-Mullerian Hormone Germ cell death Retracted cytoplasic processes Pre-Pubertal Disruption of tight junction proteins Vimentin Connexin 43

20. Mode of action? Suggested anti-androgen Testosterone changes in rats Not Mice Disruption of androgen dependent tissue Flutamide Know androgen receptor block Compare to phthalate disruption

21. Questions??