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2002 Progress Report: Impact of Phthalates on the Male: Frog and Rabbit Models
EPA Grant Number: R829429Title: Impact of Phthalates on the Male: Frog and Rabbit Models
Investigators: Veeramachaneni, D. N. Rao
Institution: Colorado State University
EPA Project Officer: Deener, Kacee
Project Period: March 1, 2002 through February 28, 2005 (Extended to February 28, 2007)
Project Period Covered by this Report: March 1, 2002 through February 28, 2003
Project Amount: $852,709
RFA: Children's Vulnerability to Toxic Substances in the Environment (2001)
Research Category: Children's Health , Health Effects
Description:
Objective:The objective of this research project is to test the hypothesis that exposure to phthalates, even at relatively low concentrations during differentiation of the reproductive system, alters the reproductive function as adults. This hypothesis is being tested in two animal models; an amphibian, Xenopus laevis, and a nonrodent mammal, the rabbit. The former facilitates transdermal exposure and evaluation of an easy-to-monitor, unique thyroid hormone-dependent event, the metamorphosis, while the latter facilitates longitudinal evaluations of hormones, semen parameters, and sexual capacity. Furthermore, rabbits, unlike rodents, have a relatively long infantile period of reproductive development that more closely approximates the situation in humans. Dermal route of exposure is particularly pertinent to children’s vulnerability to toxic substances in the environment because children have a greater ratio of surface area to body weight than adults.
Progress Summary:Reproductive sequelae were evaluated in male rabbits following exposure to dibutyl phthalate (DBP) at a dose level known to adversely affect testicular function in rodents without causing systemic toxicity. Because rabbits have a relatively long phase of reproductive development simulating better than rodents the reproductive development of humans, and because the use of rabbits facilitates multiple evaluations of mating ability and seminal quality, we used this animal model. Rabbits were exposed to 0 or 400 mg DBP/kg/day in utero (gestation days [GD] 15-29) or during adolescence (postnatal weeks [PNW] 4-12), and male offspring were examined at 6, 12, and 25 weeks of age.
Another group was exposed after puberty (for 12 weeks) and examined at the conclusion of exposure. The most pronounced reproductive effects were in male rabbits exposed in utero. Male offspring in this group exhibited reduction in numbers of ejaculated sperm (down 43 percent; p < 0.01), in weights of testes (at 12 weeks, down 23 percent; p < 0.05) and in accessory sex glands (at 12 and 25 weeks, down 36 percent; p < 0.01 and down 27 percent; p < 0.05, respectively). Serum testosterone levels were lower (at 6 weeks, 32 percent; p < 0.05); a slight increase in histological alterations of the testis (p < 0.05) and the percentage of abnormal sperm doubled (from 16 to 30 percent, p < 0.01); and 1 out of17 males manifested hypospadias, hypoplastic prostate, and cryptorchid testes with carcinoma in situ-like atypical germ cells.
In the DBP group exposed during adolescence, basal serum testosterone levels were reduced at 6 weeks (p < 0.01), while at 12 weeks, testosterone production in vivo failed to respond normally to a GnRH challenge (p < 0.01). In addition, the weight of accessory sex glands was reduced at 12 weeks, but not at 25 weeks (a recovery period); there was a slight increase in the percentage of abnormal sperm in the ejaculate and 1 out of 11 males was unilaterally cryptorchid. In both of these DBP-treated groups, daily sperm production, epididymal sperm counts, mating ability, and weights of body and nonreproductive organs were unaffected. Thus, DBP induces lesions in the reproductive system of the rabbit, with the intrauterine period being the most sensitive stage of life (Higuchi, et al., 2003).
Future Activities:We will continue to conduct experiments utilizing rabbits and frogs with a range of doses of DBP.
Journal Articles on this Report: 1 Displayed | Download in RIS Format
| Other project views: | All 16 publications | 4 publications in selected types | All 4 journal articles |
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Higuchi TT, Palmer JS, Gray Jr LE, Veeramachaneni DNR. Effects of dibutyl phthalate in male rabbits following in utero, adolescent, or postpubertal exposure. Toxicological Sciences 2003;72(2):301-313. |
R829429 (2002) R829429 (2005) R829429 (Final) |
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abnormal male sexual differentiation, atypical germ cells, carcinoma in situ, intratubular germ cell neoplasia, ejaculated sperm counts, semen quality, male reproductive development, cryptorchidism, sexual dysfunction. , Scientific Discipline, Health, RFA, Toxicology, Biology, Risk Assessments, Disease & Cumulative Effects, Health Risk Assessment, Ecological Risk Assessment, Chemistry, Children's Health, exposure assessment, risk assessment, children's environmental health, fertility, solvents, diopathic infertility, human health risk, reproductive function, exposure pathways, phtalates, children, dermal contact, frog deformities, reproductive health, reproductive development, human exposure, Human Health Risk Assessment, animal model
Progress and Final Reports:
Original Abstract
2003 Progress Report
2004 Progress Report
2005 Progress Report
Final Report