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Final Report: Endocrine Disruption in AdolescenceEPA Grant Number: R827404
Title: Endocrine Disruption in Adolescence
Investigators: Golub, Mari S. , Gershwin, M. Eric , Hendrickx, Andrew G.
Institution: University of California - Davis
EPA Project Officer: Fields, Nigel
Project Period: September 1, 1999 through August 31, 2002 (Extended to August 31, 2003)
Project Amount: $670,805
RFA: Endocrine Disruptors (1999) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Health , Safer Chemicals , Endocrine Disruptors
The objective of this research project was to determine whether estrogenic agents disrupt the timeline of female adolescent development and lead to long-term effects on reproductive, skeletal, immune, and nervous system function in a nonhuman primate.Summary/Accomplishments (Outputs/Outcomes):
Adolescence, the final stage of development, is more prolonged and complex in primates than in other species. In girls, the maturation that occurs during adolescence is orchestrated by the gonadal hormone estrogen that begins to be produced by the ovaries at puberty. Environmental toxicants that have estrogenic actions have the potential to interfere with this major developmental period that sets the stage for successful adult reproductive function. Very little is known, however, about the type and extent of influence that environmental estrogens might have on adolescent development. To address this question, we administered two estrogenic agents: diethylstilbestrol (DES), a potent pharmacological estrogen, and methoxychlor (MXC), an estrogenic pesticide, to pubertal female rhesus monkeys and examined the effects on sexual maturation. In addition, skeletal, hematologic, immune, and nervous systems were evaluated. These systems also contain estrogen receptors and mature under the influence of estrogen during adolescence.
The results of this study provide a picture of the impact of the potent estrogen, DES, on primate puberty. DES did not lead to precocious puberty or delayed puberty. Rather, pubertal development was disrupted. Somatic growth (the adolescent growth spurt) and menstruation were suppressed during dosing but resumed immediately upon cessation of dosing. Nipple growth was slowed, but sex skin changes characteristic of puberty appeared early. It is not clear whether maturation of the hypothalamic-pituitary-gonadal axis was influenced by DES because only external markers of puberty could be measured in this in vivo study.
Other data demonstrated previously known adverse effects of excess estrogen in the DES group. These included bone marrow suppression, liver damage, lipidemia, reduction of NK cell activity, reduction in bone mineralization, and reduction in auditory event- related potential latencies (e.g., auditory brain stem response [ABR]) in the brain. These effects, however, had not been documented previously in adolescence and may have particular relevance for diseases that are prominent in adolescent girls such as anemia and scoliosis, early stage cardiovascular disease, incidence of hepatitis and communicable infections associated with the onset of sexual activity, and vulnerability to induction of precancerous lesions in the breast.
Of most concern were the DES effects that did not fully recover after discontinuation of treatment. These included height, nipple volume, bone mineralization, ovarian morphology, menstrual cycle abnormalities, serum cholesterol, ABR latencies, neutrophil counts, and serum cholesterol. This finding carries the implication that systems regulated by estrogen were permanently altered because of the estrogen exposure during this critical developmental period. These alterations may have implications for adult disorders such as infertility, autoimmune disease susceptibility, metabolic syndrome, cardiovascular disease, reproductive tract cancer, and osteoporosis. Environmental factors are known to contribute to the incidence of these major diseases, but the effects of exposures to environmental toxicants, particularly exposures during adolescence, are just beginning to be explored.
A special aspect of our research project was the evaluation of cognitive performance through behavioral testing during and after dosing with estrogenic agents. The final stages of cognitive development take place during adolescence, including the ability for abstract thought and sophisticated logical reasoning. Corresponding to the attainment of these abilities is the completion of formal education. We are suggesting that environmental agents, including environmental estrogens, could interfere with school performance and achievement in adolescent girls. School performance is of great concern and is very commonly assessed in longitudinal studies of children. Environmental agents such as lead, mercury, and polychlorinated biphenyls have been associated with cognitive dysfunction in children, and this effect has played a major role in risk assessment and risk management of these agents. Our studies looked at two simple tasks: visual discrimination and spatial working memory. Although this work is in a very early stage, it did demonstrate effects of the estrogenic agents.
A major finding of this study was that MXC led to qualitatively, rather than quantitatively, different effects than DES. MXC, at least at the doses administered, had minimal effects on adolescent growth and markers of puberty. Notably, DES did not influence performance of cognitive tasks, but MXC was effective in this regard. MXC also led to a shorter follicular phase of the menstrual cycle after treatment was discontinued; DES led to a shorter luteal phase. Although DES influenced many parameters of clinical chemistry that were not responsive to MXC, it did not influence electrolytes, whereas electrolytes were transiently elevated after MXC treatment was initiated. The higher MXC dose, like DES, led to reduced bone mineralization and shorter ABR latencies. In cases where MXC acted similarly to DES, it generally was the case that the lower MXC dose (MXC25) was effective, rather than the high dose (MXC50).
These findings argue against a single syndrome resulting from estrogenic exposures during puberty. They are in agreement with the growing evidence for a variety of receptors and nonreceptor response mechanisms available to mediate estrogenic effects in different tissues. Agents, which generally can be said to be “estrogenic,” interact with these response mechanisms in qualitatively and quantitatively different ways. We have generated a hypothesis involving estrogen actions at different receptor types (ERα and ERβ) to account for our findings and guide further work. In addition, we hope to follow this cohort of treated monkeys in to adulthood and assess the impact of the estrogenic exposures on fertility and health.
Implications for Public Health
The goal of environmental toxicology is to predict and prevent adverse health effects that result from exposure to toxicants in environmental media. Programs designed to deal with the potential threat of endocrine disruptors, such as the Endocrine Disruptor Screening and Testing Advisory Committee, have focused on screening chemicals for endocrine disrupting ability as a basis for risk assessment. Our project complements these activities by providing unique information on endocrine disruption during an important life stage (adolescence) in an appropriate animal model (nonhuman primate). It bridges the gap between research on screening and human population studies, and hopefully will contribute to the success and efficiency of the goal of preventing public health impacts of endocrine disrupting chemicals.
A grant proposal based on this research project was submitted to the National Institutes of Health in July 2003, but was not funded. A Mouse Genome Informatics revision of the proposal based on reviewer’s comments may be prepared during the coming year. The cohort of monkeys was entered into the colony-breeding program in fall 2003, and their reproductive success will be followed in the colony database.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
|Other project views:||All 16 publications||4 publications in selected types||All 4 journal articles|
|| Golub MS. Cognitive testing (delayed non-match to sample) during oral treatment of female adolescent monkeys with the estrogenic pesticide methoxychlor. Neurotoxicology and Teratology 2002;24(1):87-92.
|| Golub MS, Hogrefe CE, Germann SL, Lasley BL, Natarajan K, Tarantal AF. Effects of exogenous estrogenic agents on pubertal growth and reproductive system maturation in female rhesus monkeys. Toxicological Sciences 2003;74(1):103-113.
|| Golub MS, Germann SL, Hogrefe CE. Endocrine disruption and cognitive function in adolescent female rhesus monkeys. Neurotoxicology and Teratology 2004;26(6):799-809.
|| Golub MS, Hogrefe CE, Germann SL, Jerome CP. Endocrine disruption in adolescence: immunologic, hematologic, and bone effects in monkeys. Toxicological Sciences 2004;82(2):598-607.
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