And Environmental Androgens and Antiandrogens

L. Earl Gray Jr.Christy Lambright2, Louise ParksRochelle W. Tyl2, Edward F. Orlando3, Louis J. Guillette Jr.3, Cynthia J. Wolf1, John C. Seely4, Tsai-Yin Chang2, Vickie Wilson5, Andrew Hotchkiss5, Joseph S. Ostby1

1 Endocrinology Branch, Reproductive Toxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA

E-mail: [email protected], [email protected]

2 Research Triangle Institute, Research Triangle Park, North Carolina, USA

3 University of Florida, Zoology Dept, Gainesville, Florida, USA

4 Pathco, Research Triangle Park, North Carolina, USA

5 North Carolina State University/US Environmental Protection Agency Cooperative Research Program

Disclaimer. The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U. S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Wildlife populations from contaminated ecosystems display a variety of reproductive alterations including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. In some cases, clear cause and effect relationships exist between exposure to endocrine disrupting chemicals (EDCs) and adverse effects in fish, wildlife, and domestic animals. The formation of biologically plausible hypotheses regarding toxicant-induced disruption of reproduction can be facilitated by definitive mechanistic rodent studies. To this end, we have investigated the in vivo and in vitro effects of suspect antiandrogenic and dioxin-like substances. In vivo studies examined short-term effects, effects on puberty, and toxicant-induced alterations of rat sexual differentiation. We utilize short-term in vivo and in vitro assays (receptor binding, transfected cell, and steroidogenesis assays) in order to confirm the suspected mechanism of action. To date, in vitro and in vivo studies have identified several antiandrogenic toxicants including vinclozolin, procymidone, linuron, several phthalate esters, and p,p'-DDE, all of which alter male rat sex differentiation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the TCDD-like congener PCB 169 affect both male and female offspring, inducing dramatic reductions in ejaculated sperm numbers at low dosage levels. In utero exposure to antiandrogenic and TCDD-like chemicals result in profiles of effects in the offspring that are pathognomonic for each mechanism of action. Mechanistic information from rodent studies using dosing regimes that produce relevant toxicant tissue levels, coupled with an understanding of the endocrine factors regulating reproductive development in the species of concern, can enhance our ability to predict the effects of EDCs on human and wildlife reproduction. For some EDCs (i.e., PCBs, PCDDs, PCDFs, or p,p'-DDE), developmental effects are seen in rats using dosing regimes that produce fetal exposure levels that appear to be within the reported range of some segments of the human population.

Keywords. Sexual differentiation, Androgens, Dioxins, PCBs Vinclozolin, Procymidone, DDT and DDE, Linuron, Pesticides, Toxic substances, Pulp mill effluent, Intersex

The Handbook of Environmental Chemistry Vol. 3, Part M

Endocrine Disruptors, Part II

© Springer-Verlag Berlin Heidelberg 2002

1 Introduction 212

2 Effects of Endocrine Disrupting Chemicals (EDCs) 215

2.1 Cause-and-Effect Relationships for EDCs 216

2.2 Known Effects of Drugs on Human Sexual Differentiation 217

2.3 Known Effects of Plant and Fungal Estrogens in Animals and Humans 217

2.4 Known Effects of Plant Antiandrogens in Humans and Rodents . .218

2.5 Known Effects of Pesticides and Toxic Substances on Endocrine Function and/or Reproduction in Humans 219

2.5.1 Known Effects of PCBs, PCDDs, and PCDFs in Humans 219

2.5.2 Known Effects of DDTs in Humans 219

2.5.3 Occupational Exposure to Chlordecone and Dibromochloropropane 219

2.5.4 Occupational Exposure to Amsonic Acid 220

3 Environmental Androgens Revealed 220

4 Potential Effects of Toxicants on Sex Ratio in Humans and Animals 221

5 Vinclozolin 225

5.1 In Vitro and In Vivo Effects 225

5.2 Dose-Response of Developmental Effects 225

5.3 Effects During Puberty 226

5.4 Effects on the Liver and Adrenal 227

5.5 Effects in Lower Vertebrates 228

6 Procymidone 228

6.1 In Vitro Effects 228

6.2 Dose-Response of Developmental Effects 229

7 Linuron 229

7.1 In Vitro and Short-Term In Vivo Effects 229

7.2 Developmental Effects 230

8 DDT and DDE 231

8.1 Background 231

8.2 In Vitro and Developmental/Reproductive Effects ofp,p'-DDE . . . 231

8.3 Potential Antiandrogenic Effects of p,p'-DDE in Wildlife 232

8.4 Endocrine Mechanisms of Eggshell Thinning 232

8.5 p,p'-DDE and Lake Apopka Alligators and Birds 233

9 Antiandrogenic Effects of Phthalate Esters During Development . . 235

10 Polychlorinated Aromatic Compounds

10.2 PCB 169: A Putative Antiandrogen? . .

11 Inhibitors of Steroid Hormone Synthesis

11.1 Ketoconazole

11.2 Fenarimol

12 Conclusions

13 References

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