Section of Neurobiology, Physiology and Behavior, University of California at Davis, Davis, CA 95616, USA.
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Abstract |
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Key words: genetics/endocrine disruption/oestrogen/sensitivity/xenobiotics
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Introduction |
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While many excellent laboratory animal studies have established that several environmental compounds are oestrogenic, and can disrupt reproductive development and function, the vast majority of these studies have been conducted in a small number of `outbred' lines of mice and rats that were developed primarily by long-term selective breeding for high fecundity (large litter size) and vigour (rapid growth rate). Although some of the highly prolific outbred strains have been selected more recently for intermediate litter size and vigour, current but limited evidence suggests that these strains remain relatively resistant to oestrogenic agents. In fact, recent studies have revealed a tremendous amount of genetic variation in susceptibility to endocrine disruption by oestrogenic agents (SEDE) between strains of mice and rats (Steinmetz et al., 1997, 1998
; Spearow et al., 1999
, 2000
). These studies have shown that the highly prolific, large litter size selected CD-1 mice and SpragueDawley rats most commonly used for product-safety testing are much more resistant to oestrogenic agents than other strains examined. For example, CD-1 mice are well over 16-fold more resistant than C57BL/6J (B6) and other strains of mice to the inhibition of testes weight, total accessory gland weight, and sperm maturation (Spearow et al., 1999
). Most importantly, CD-1 is estimated to be about 126-fold more resistant than B6 mice to the inhibition by oestradiol of sperm maturation to the elongated spermatid stage of development.
Prolific outbred CD-1 and/or ICR line mice are also less sensitive than B6 and other unselected strains of mice to the uterotropic effects of potent oestrogens including DES and oestradiol benzoate (Farmakalidis and Murphy, 1984a; Spearow et al., 1999
) as well as weak phytoestrogens (Farmakalidis and Murphy, 1984b
; Farmakalidis et al., 1985
). Inbred strains of mice also differ dramatically in susceptibility to the neonatal induction of testicular disorganization and necrosis and severe inflammation by tamoxifen (Nakai et al., 1999
). The most favoured EPA rodent model for endocrine disruptor testing, the SpragueDawley rat, is also more resistant than other strains to the inhibition of testis weight by diesthylstiboestrol (DES) (Inano et al., 1996
). Furthermore, SpragueDawley rats are highly resistant while Fisher-344 rats are highly sensitive to oestradiol, DES or BisPhenol A induced hyperprolactinaemia, uterine and vaginal hypertrophy, hyperplasia, mucous secretion and c-Fos induction (Steinmetz et al., 1997
, 1998
).
These findings in pubertal and adult animals indicate that prolific CD-1 mice and SpragueDawley derived rats are more resistant than other strains of mice and rats to the disruption of reproductive development and function by oestrogenic agents. Furthermore, these strain differences in sensitivity are found in bioassays which are similar to several of the Tier-1 bioassays to be used by the EPA for screening tens of thousands of chemicals for oestrogenic effects. The documentation of a large amount of genetic variation in susceptibility to endocrine disruption by oestrogen (SEDE) between strains of mice and rats suggests that there is likely to be a large amount of genetic variation in this trait in other species as well.
Unfortunately, the national toxicology programme (NTP) of the USA has routinely used large litter size selected, highly prolific CD-1 mice and (CD) SpragueDawley rats for testing the disrupting effects of various chemicals on reproductive endocrine function (RACB Study Abstracts, 1998). Furthermore, the US EPA was planning to use the highly prolific, large litter size selected, (CD) SpragueDawley rat in its endocrine disrupter screening programme. If these strains really are as resistant to oestrogenic agents as preliminary data suggests, safety tests of oestrogenic chemicals using large litter size selected `outbred' lines of laboratory animals may greatly underestimate the disruption of reproductive development and function of oestrogen sensitive genotypes (Spearow et al., 1999
). Broad variation in sensitivity to oestrogen is likely in most vertebrate populations and species, including humans. For example, extreme genetic differences in sensitivity to oestrogenic effects on reproductive function and behaviour have already been found in vertebrates ranging from reptiles to rodents and other mammals (Land, 1976
; Compaan et al., 1993
; Young et al., 1995
). This genetic variation in sensitivity to oestrogens supports other observations of a wide range of genetic variation in sensitivity to non-oestrogenic reproductive toxicants (Magnusson and Ramel, 1986
; Jana et al., 1998
; O'Connor et al., 1999
). Thus, the genetic sensitivity of the animal model used for testing the endocrine disruptor activity of oestrogenic chemicals is unequivocally important.
We should realize that an animal that has been selected for high fecundity regulates reproduction quite differently than unselected individuals. Furthermore, these highly prolific strains tend to be quite precocious, with many `immature' CD-1 females showing vaginal opening and elevated uterine weights even in response to the 0 dose control treatment (Spearow et al., 2000). Such precocious sexual development and the resulting elevation of ovarian oestrogen production complicates, if not limits, the use of strains previously selected for high prolifacy for detecting oestrogenic activities with intact uterotrophic assays.
Given the high level of resistance to oestrogenic agents of currently used, highly prolific animal models, care is needed to protect not only the average but also the genetically most sensitive individuals, populations and species from harm by endocrine disrupting chemicals. Using oestrogen resistant strains for product safety testing could allow elevated environmental release rates of biologically active agents which could inappropriately disrupt the reproductive development and function of sensitive genotypes. This could result in an early, avoidable demise of sensitive individuals, populations and species. Thus, it is critical that the EPA, NTP and other governmental testing agencies consider the range of genetic sensitivity to endocrine disruption and adopt the use of sensitive animal models in screening chemicals for endocrine disrupting effects. The intersexuality, decreased gametogenesis and perhaps decreased fecundity following the exposure of fish and wildlife populations to endocrine disrupting chemicals (EDC) suggests that this approach is already overdue (Tyler et al., 1998; Matthiessen, 2000
).
Even though the National Institute of Health (NIH) and the EPA were urged for several years to consider the role of genetic differences in SEDE, prior to the low dose endocrine disruptor peer review (NIEHS, 2000), neither the NTP nor the EPA was prepared to consider the role of genetic differences in SEDE. Fortunately, the National Science Foundation Ecological and Evolutionary Physiology Program recognized this critical need and provided grant funding to determine the physiological mechanisms mediating genetic differences in SEDE.
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Acknowledgements |
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Notes |
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References |
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Farmakalidis, E. and Murphy, P. (1984a) Different oestrogenic responses of ICR, B6D2F1 and B6C3F1 mice given diesthylstiboestrol orally. Food Chem. Toxic., 22, 681682.[ISI][Medline]
Farmakalidis, E. and Murphy, P. (1984b) Oestrogenic response of the CD-1 mouse to the soya-bean isoflavones genistein, genistin and daidzin. Food Chem. Toxic., 22, 237239.[ISI][Medline]
Farmakalidis, E., Hathcock, J. and Murphy, P. (1985) Oestrogenic potency of genistin and daidzin in mice. Food Chem. Toxic., 23, 741745.[ISI][Medline]
Inano, H., Suzuki, K., Onoda, M. and Wakabayashi, K. (1996) Relationship between induction of mammary tumors and change of testicular functions in male rats following gamma-ray irradiation and/or diethylstilbestrol. Carcinogenesis, 17, 355360.[Abstract]
Jana, N.R., Sarkar, S., Yonemoto, J. et al. (1998) Strain differences in cytochrome P4501A1 gene expression caused by, 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator. Biochem. Biophys. Res. Commun., 248, 554558.[ISI][Medline]
Jobling, S., Reynolds, T. White, R. et al. (1995) A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ. Health Perspect., 103, 582587.[ISI][Medline]
Land, R.B. (1976) The sensitivity of the ovulation rate of Finnish landrace and blackface ewes to exogenous oestrogen. J. Reprod. Fertil., 48, 217218.[Medline]
Magnusson, J. and Ramel, C. (1986) Genetic variation in the susceptibility to mercury and other metal compounds in Drosophila melanogaster. Teratog. Carcinog. Mutagen., 6, 289305.[ISI][Medline]
Matthiessen, P. (2000) Hormones and endocrine disrupters in aquatic environment. hormone and endocrine disrupters in food and water: possible impact on human health. Rigshospitalet, Copenhagen, Denmark.
Nakai, M., Uchida K. and Teuscher, C. (1999) The development of male reproductive organ abnormalities after neonatal exposure to tamoxifen is genetically determined. J. Androl., 20, 626634.
O'Connor, J.C., Frame, S.R., Davis, L.G. and Cook, J.C. (1999) Detection of the environmental antiandrogen p,p*-DDE in CD and long-evans rats using a tier I screening battery and a Hershberger assay. Toxicol. Sci., 51, 4453.[Abstract]
NIEHS (2000). NTP/NIEHS Endocrine Disruptors Low Dose Peer Review, October 1012, 2000, Research Triangle Park, North Carolina, National Toxicology Program/National Institutes of Environmental Health Sciences. http://ntp-server.niehs.nih.gov/htdocs/liason/LowDoseWebPage.html
RACB Study Abstracts (1998). Reproductive Assessment by Continuous Breeding Reproductive Toxicity Study Abstracts. NTB Publications. http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html
Sonnenschein, C. and Soto, A.M. (1998) An updated review of environmental estrogen and androgen mimics and antagonists. J. Steroid Biochem. Mol. Biol., 65, 143150.[ISI][Medline]
Spearow, J.L., Doemeny, P., Sera, R. et al. (1999) Genetic variation in susceptibility to endocrine disruption by estrogen in mice. Science, 285, 12591261.
Spearow, J.L., Sofos, T., O'Henley, P. et al. (2000) Genetic variation in sensitivity to endocrine disruption by estrogenic agents. Second Annual UC Davis Conference for Environmental Health Scientists, The Embassy Suites, Napa, CA, USA.
Steinmetz, R., Brown, N.G., Allen, D.L. et al. (1997) The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology, 138, 17801786.
Steinmetz, R., Mitchner, N.A., Grant, A. et al. (1998) The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract. Endocrinology, 139, 27412747.
Tyler, C.R., Jobling, S. and Sumpter, J.P. (1998) Endocrine disruption in wildlife: a critical review of the evidence. Critical Reviews in Toxicology, 28, 319361.[ISI][Medline]
vom Saal, F.S., Cooke, P.S., Buchanan, D.L. et al. (1998) A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicology and Industrial Health, 14, 239260.[ISI][Medline]
Young, L.J., Nag, P.K. and Crews, D. (1995) Species differences in behavioral and neural sensitivity to estrogen in whiptail lizards: correlation with hormone receptor messenger ribonucleic acid expression. Neuroendocrinology, 61, 680686.[ISI][Medline]
Submitted on December 19, 2000; accepted on February 2, 2001.