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Endocrine Active Agents: Implications of Adverse and Non-Adverse Changes

CT Centers for Health Research, Research Triangle Park, North Carolina 27709 USA, foster{at}ciit.org

Barry S. Mcintyre

CT Centers for Health Research, Research Triangle Park, North Carolina 27709 USA

The US Environmental Protection Agency (EPA) is currently in the process of developing screening and testing methodologies for the assessment of agents that may possess endocrine-like activity—the so-called endocrine disruptors. Moreover, the EPA has signaled its intention of placing information arising from such studies on the worldwide web. This has created significant interest in how such information may be used in risk assessment and by policymakers and the public in the potential regulation or deselection of specific chemical agents. The construction of lists of endocrine disruptors, although fulfilling the requirements of some parties, is really of little use when the nature of the response, the dose level employed, and the lifestage of the test species used are not given. Thus, we have already seen positive in vitro information available on the interaction with a receptor being used as a key indicator when the results of large, high quality in vivo studies showing no adverse changes have been ignored. Clearly a number of in vitro systems are available to ascertain chemical interaction with specific (mainly steroid) hormone receptors including a number of reporter gene assays. These assays only provide indicators of potential problems and should not be, in isolation, indicators of toxicity. Likewise, short-term in vivo screens such as the uterotrophic and Hershberger studies are frequently conducted in castrated animals and thus indicate the potential for a pharmacological response in vivo rather than an adverse effect. A number of new end points have been added to standard rodent testing protocol s in the belief of providing more sensitivity to detect endocrine related changes. These include the measurement of anogenital distance (AGD), developmental landmarks [vaginal opening (VO), preputial separation (PPS)], and in some studies the counting of nipples and areolae on males. AGD, VO, and PPS are all affected by the size of the pup in which they are measured and should always be compared using bodyweight as a covariate. The historical control database for such changes is gradually growing, albeit that if pups are not individually identified it becomes problematic to associate any change with a specific malformation or to assess whether a delay or advance in, for example, developmental landmarks is biologically significant. Agents that significantly reduce AGD in males (it is an androgen-dependent variable) frequently have other more adverse changes associated with this end point (eg, reproductive tract malformations), but a 2 to 3% change in AGD although measurable is unlikely to be biologically of importance and in isolation would not necessarily be considered adverse. Retention of thoracic nipples in male rat pups is also an indicator of impaired androgen status. Recent studies have also shown that this retention for some endocrine active chemicals is permanent. Thus, the presence of a permanent structural change that is rarely found in adult control animals could be considered a malformation and therefore a developmental adverse effect on which risk assessment decisions could be made. The advent of multigeneration reproduction studies as the definitive studies for the assessment of the dose-response relationships and risk assessment for endocrine disruptors has shown that current testing protocols may be inadequate to reliably detect the adverse effects of concern as only 1 adult/sex/litter is examined. A number of the effects on reproductive development although, due to an in utero exposure, will not be manifest until after puberty or at adulthood. The use of only a limited number of animals to examine such changes, particularly for weaker acting materials indicates that some agents may have been examined in well-conducted, modern protocols but have insufficient power to detect low incidence phenomena (eg, a 5% incidence of malformations).

Key Words: Antiandrogen • linuron • flutamide • development (androgen-dependent) • anogenital distance • nipple retention • reproductive development.

References

• Berman DM, Tian H., Russell DW (1995). Expression and regulation of steroid 5 alpha-reductase in the urogenital tract of the fetal rat. Mol Endocrinol 9: 1561—1570.[Abstract/Free Full Text]
• Clark RL, Anderson CA, Prahalada S., Robertson RT, Lochry EA, Leonard YM, Stevens JL, Hoberman AM (1993). Critical developmental periods for effects on male rat genitalia induced by fi nasteride, a 5 alpha-reductas e inhibitor. Toxicol Appl Pharmacol 119: 34—40.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Clark RL, Antonello JM, Grossman SJ, Wise LD, Anderson C., Bagdon WJ, Prahalada S., MacDonald JS, Robertson RT (1990). External genitalia abnormalities in male rats exposed in utero to fi nasteride, a 5 alpha-reductas e inhibitor. Teratology 42: 91—100.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Cook JC, Mullin LS, Frame SR, Biegel LB (1993). Investigation of a mechanism for Leydig cell tumorigenesi s by linuron in rats. Toxicol Appl Pharmacol 119: 195—204.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Foster WG (1998). Endocrine disruptors and development of the reproductive system in the fetus and children: Is there cause for concern? Can J Public Health Revue Canadienne De Sante Publique 89 Suppl 1: S37—41, S52, S41—6.
• Gray L. Jr, Kelce WR (1996). Latent effects of pesticides and toxic substances on sexual differentiation of rodents. Toxicol Indus Health 12: 515—531.[Abstract/Free Full Text]
• Gray LE, Ostby J., Furr J., Price M., Veeramachaneni DN, Parks L. (2000). Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58: 350—365.[Abstract/Free Full Text]
• Gray LE, Ostby JS, Kelce WR (1994). Developmental effects of an environmental antiandrogen: The fungicide vinclozolin alters sex differentiation of the male rat. Toxicol Appl Pharmcol 129: 46—52.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Gray LE Jt, Ostby J., Wolf C., Lambright C., Kelce W. (1998). The value of mechanistic studies in laboratory animals for the prediction of reproductive effects in wildlife: Endocrine effects on mammalian sexual differentiation. Environ Toxicol Chem 17: 109—118.[CrossRef][Web of Science]
• Gray LE Jr, Wolf C., Lambright C., Mann P., Price M., Cooper RL, Ostby J. (1999). Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexy l phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profi les of reproductive malformations in the male rat. Toxicol Indus Health 15: 94—118.[Abstract/Free Full Text]
• Hecker A., Hasan SH, Neumann F. (1980). Disturbances in sexual differentiation of rat foetuses following spironolactone treatment. Acta Endocrinol (Copenh) 95: 540—545.[Abstract/Free Full Text]
• Imperato-McGinley J., Binienda Z., Gedney J., Vaughan ED Jr (1986). Nipple differentiation in fetal male rats treated with an inhibitor of the enzyme 5 alpha-reductase: Defi nition of a selective role for dihydrotestosterone. Endocrinology 118: 132—137.[Abstract/Free Full Text]
• Imperato-McGinley J., Sanchez RS, Spencer JR, Yee B., Vaughan ED (1992). Comparison of the effects of the 5 alpha-reductase inhibitor fi nasteride and the antiandrogen fl utamide on prostate and genital differentiation: Dose-response studies. Endocrinology 131: 1149—1156.[Abstract/Free Full Text]
• Kassim NM, McDonald SW, Reid O., Bennett NK, Gilmore DP, Payne AP (1997). The effects of pre- and postnatal exposure to the nonsteroidal antiandrogen fl utamide on testis descent and morphology in the Albino Swiss rat. J Anat 190 (Pt4): 577—588.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kelce WR, Gray LE, Wilson EM (1998). Antiandrogens as environmental endocrine disruptors. Reprod Fertil Dev 10: 105—111.[CrossRef][Medline] [Order article via Infotrieve]
• Kelce WR, Lambright CR, Gray Le J, Roberts KP (1997). Vinclozolin and p,p'-DDE alter androgen-dependen t gene expression: In vivo confi rmation of an androgen receptor-mediated mechanism. Toxicol Appl Pharmacol 142:192—200.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kratochwil K. (1971). In vitro analysis of the hormonal basis for the sexual dimorphism in the embryonic development of the mouse mammary gland. J Embry Exp Morph 25: 141—153.
• Kratochwil K. (1977). Development and loss of androgen responsiveness in the embryonic rudiment of the mouse mammary gland. Dev Biol 61: 358—365.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kratochwil K. (1986). Tissue combination and organ culture studies in the development of the embryonic mammary gland. Dev Biol (NY 1985) 4:315—333.
• Kratochwil K., Schwartz P. (1976). Tissue interaction in androgen response of embryonic mammary rudiment of mouse: Identifi cation of target tissue for testosterone. Proc Natl Acad Sci USA 73: 4041—4044.[Abstract/Free Full Text]
• LambrightC., Ostby J., Bobseine K., Wilson V., Hotchkiss AK, Mann PC, Gray LE Jr (2000). Cellular and molecular mechanisms of action of linuron: An antiandrogenic herbicide that produces reproductive malformations in male rats. Toxicol Sci 56: 389—399.[Abstract/Free Full Text]
• LeBlanc GA, Bain LJ, Wilson VS (1997). Pesticides: Multiple mechanisms of demasculinization. Mol Cell Endocrinol 126: 1—5.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• McIntyre BS, Barlow NJ, Foster PMD (2001). Androgen-mediated development in male rat offspring exposed to fl utamide in utero: Permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependen t tissues. Toxicol Sci (in press).
• McIntyre BS, Barlow NJ, Wallace DG, Maness SC, Gaido KW, Foster PMD (2000). Effects of in utero exposure to linuron on androgen-dependen t reproductive development in the male Crl:CD(SD)BR rat. Toxicol Appl Pharmacol 167: 87—99.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mylchreest E., Cattley RC, Foster PM (1998). Male reproductive tract malformations in rats following gestational and lactational exposure to Di(n-butyl) phthalate: An antiandrogenic mechanism? Toxicol Sci 43: 47—60.[Abstract/Free Full Text]
• Mylchreest E., Sar M., Cattley RC, Foster PM (1999). Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from fl utamide. Toxicol Appl Pharmacol 156: 81—95.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Nagao T., Ohta R., Marumo H., Shindo T., Yoshimura S., Ono H. (2000). Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: A two-generation reproductive study. Reprod Toxicol 14: 513— 532.
• Ostby J., Kelce WR, Lambright C., Wolf CJ, Mann P., Gray LE Jr (1999). The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-recepto r antagonist in vivo and in vitro. Toxicol Indus Health 15: 80—93.[Abstract/Free Full Text]
• Roy AK, Chatterjee B. (1995). Androgen action. Crit Rev Eukaryot Gene Expr 5: 157—176.[Web of Science][Medline] [Order article via Infotrieve]
• Schardein J. (1993). Hormones and Hormone Antagonists. Marcel Dekker, New York.
• Sharpe RM, Skakkebaek NE (1993). Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? [see comments]. Lancet 341: 1392—1395.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Silversides DW, Price CA, Cooke GM (1995). Effects of short-term exposure to hydroxyflutamide in utero on the development of the reproductive tract in male mice. Can J Physiol Pharmacol 73: 1582—1588.[Web of Science][Medline] [Order article via Infotrieve]
• Toppari J., Larsen JC, Christiansen P., Giwercman A., Grandjean P., Guillette LJ Jr, Jégou B., Jensen TK, Jouannet P., Keiding N., Leffers H., McLachlan JA, Meyer O., Müller J., Rajpert-De Meyts E, Scheike T, Sharpe R, Sumpter J, Skakkebaek NE (1996). Male reproductive health and environmental xenoestrogens. Environ Health Perspect 104 Suppl 4: 741—803.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• United States Environmental Protection Agency (US EPA) (1998a). EDSTAC Final Report.
• United States Environmental Protection Agency (US EPA) (1998b). Health Effects Test Guidelines OPPTS 870.3800 Reproduction and Fertility Effects. EPA 712C: 1—12.
• Veyssiere G., Berger M., Jean-Faucher C., de Turckheim M., Jean C. ( 1982). Testosterone and dihydrotestosterone in sexual ducts and genital tubercle of rabbit fetuses during sexual organogenesis: Effects of fetal decapitation. J Steroid Biochem 17: 149—154.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Waterman SJ, Keller LH, Trimmer GW, Freeman JJ, Nikiforov AI, Harris SB, Nicolich MJ, McKee RH (2000). Two-generation reproduction study in rats given di-isononyl phthalate in the diet. Reprod Toxicol 14: 21—36.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• WilsonJD,Lasnitski I. (1971). Dihydrotestosteroneformationinfetal tissues of the rabbit and rat. Endocrinology 89: 659—668.[Abstract/Free Full Text]
• You L., Casanova M., Archibeque-Engle S., Sar M., Fan LQ, Heck HA ( 1998). Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p'-DDE. Toxicol Sci 45: 162—173.[Abstract/Free Full Text]

Toxicologic Pathology, Vol. 30, No. 1, 59-65 (2002)
DOI: 10.1080/01926230252824716


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This article has been cited by other articles:

				R. H. McKee Comments on Foster, P., and McIntyre, B. (2002). Endocrine Active Agents: Implications of Adverse and Non-Adverse Changes. Toxicol Pathol 30(1): 59--65 Toxicol Pathol, October 1, 2002; 30(6): 755 - 756. [PDF]

				P. M. D. Foster Response to Comments of Richard H. McKee. Toxicol Pathol 30(6): 755--756 Toxicol Pathol, October 1, 2002; 30(6): 757 - 757. [PDF]

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