The long-term objective of this research is to determine the mechanism(s) by which dioxin like environmental contaminants affect fertility in females. TCDD, a potent dioxin, has long been known to be a reproductive toxin in subhuman primates and rodents; however, little is known about reproductive outcomes in exposed human populations. In order to evaluate possible effects in humans, a goal of this research is to develop and characterize animal models that show decreased fertility as a result of low-level exposure perinatally and/or in adulthood. To address this question, regional distribution of genes encoding the arylhydrocarbon receptor (AhR; R for TCDD) and its companion protein AhR nuclear translocator (Arnt) in brain was examined. Both genes were found to be expressed in brain regions that have estrogen receptors (ER), which play a crucial role in regulating LH release. These data support that TCDD and related chemicals may interfere with neural actions of estrogen (and its induction of ovulation). AhR and Arnt genes were also found to be expressed in ER-containing regions of the hypothalamus of embryos, supporting possible transplacental effects. The working hypothesis is that: TCDD affects fertility by interfering with estrogen-induced hypothalamic/POA events that trigger LHRH, thus LH surge release. A dose-response study will be performed using environmentally-relevant levels of TCDD, to determine whether perinatal, prepubertal and adult exposure inhibit the ability of estrogen to induce LH release. Ovariectomized, estrogen-treated rats will be used to eliminate ovarian effects of TCDD. Other studies will determine whether local microimplants of TCDD affect LH release when placed in the brain structures known to contain both AhR and ER. Finally, a determination as to whether TCDD alters the ability of the pituitary gland to release LH in response to LHRH will be made.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008774-02
Application #
2872334
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1998-02-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153223151
City
Amherst
State
MA
Country
United States
Zip Code
01003
Intlekofer, K A; Petersen, S L (2011) 17?-estradiol and progesterone regulate multiple progestin signaling molecules in the anteroventral periventricular nucleus, ventromedial nucleus and sexually dimorphic nucleus of the preoptic area in female rats. Neuroscience 176:86-92
Cao, Jinyan; Patisaul, Heather B; Petersen, Sandra L (2011) Aryl hydrocarbon receptor activation in lactotropes and gonadotropes interferes with estradiol-dependent and -independent preprolactin, glycoprotein alpha and luteinizing hormone beta gene expression. Mol Cell Endocrinol 333:151-9
Intlekofer, K A; Petersen, S L (2011) Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience 172:55-65
Petersen, Sandra L; Krishnan, Sudha; Hudgens, Edward D (2006) The aryl hydrocarbon receptor pathway and sexual differentiation of neuroendocrine functions. Endocrinology 147:S33-42
Hays, Linda E; Carpenter, Clifford D; Petersen, Sandra L (2002) Evidence that GABAergic neurons in the preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin during development. Environ Health Perspect 110 Suppl 3:369-76
Petersen, S L; Curran, M A; Marconi, S A et al. (2000) Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem. J Comp Neurol 427:428-39