Low Dose Effects of In Utero Exposure to Cadmium on PubertyEPA Grant Number: R832136
Title: Low Dose Effects of In Utero Exposure to Cadmium on Puberty
Investigators: Martin, Mary Beth , Hilakivi-Clarke, Leena , Lumpkin, Michael
Institution: Georgetown University
EPA Project Officer: Hahn, Intaek
Project Period: December 1, 2004 through November 30, 2007 (Extended to November 30, 2009)
Project Amount: $738,798
RFA: Development and Characterization of Biological Systems for Studying Low Dose Effects of Endocrine Disrupting Chemicals (2004) RFA Text | Recipients Lists
Research Category: Endocrine Disruptors , Environmental Justice , Safer Chemicals
During the last century, the onset of puberty and menarche in girls in the U.S. has occurred at significantly younger ages. Recent studies from our laboratory show that heavy metal cadmium has potent estrogen-like activity in vivo and that in utero exposure to environmentally relevant amounts of the metal advances the onset of puberty, increases weight gain, and alters the development of the mammary gland in female rat offspring.
This application will test the hypothesis that in utero exposure to low doses of cadmium alters the hypothalamic-pituitary-gonadal axis and consequently alters the onset of puberty, predisposes to obesity, and accelerates the development of the mammary gland. Objective 1 will determine the dose-response effects of in utero exposure to cadmium on the onset of puberty, weight gain, and mammary gland development. More specifically, objective 1 will determine whether there is a linear relationship between the in utero exposure to low doses of cadmium and estrogen like effects in female offspring. Objective 2 will determine the mechanism by which in utero exposure to cadmium alters the onset of puberty. Objective 3 will determine the mechanism by which in utero exposure to cadmium alters weight gain. Objective 4 will determine the mechanism by which in utero exposure to cadmium accelerates the development of the mammary gland.
To achieve these goals: Objective 1 will determine whether there is a linear relationship between the in utero exposure to low doses of cadmium (0.05, 0.5, 5, 50 and 500 ng/kgbw) and the estrogen like effects on puberty onset, body weight, and mammary gland development in female offspring. Two hypotheses have been proposed for the regulation of the onset of puberty. The gonadostat hypothesis proposes that the onset of puberty is due to a decreased sensitivity of the hypothalamus to the negative feedback of gonadol steroids, whereas the intrinsic restraint hypothesis proposes that the onset of puberty is regulated by the production of stimulatory signals [glutamate, neuropeptide Y (NPY), and transforming growth factor-alpha (TGFa)] that override the inhibitory signal [gamma-aminobutyric acid (GABA)] in the hypothalamus. Objective 2 is designed to determine whether in utero exposure to cadmium alters either or both of these pathways. Energy homeostasis is also controlled by the hypothalamus. Objective 3 will determine whether in utero exposure to cadmium alters the development and/or the responsiveness of the hypothalamus to endocrine [gherlin, PYY3-36, insulin, and leptin] and neuronal [NPY and agouti-related peptide (AgRP)] signals. Objective 4 will then determine whether cadmium alters the development of the mammary gland in utero or whether the metal alters the onset of puberty and consequently the development of the gland.
Endocrine related diseases have reached or are reaching epidemic levels in Western populations such as the United States; however, the underlying causes of these diseases are not fully understood. We have recently identified metals as potent endocrine disruptors with estrogen-like activity. Our understanding of the potential significance of this finding to human populations is still in its infancy. In this application, we propose to study the estrogen like effects of cadmium, as a prototype of bivalent metals, at doses that are environmentally relevant.