Grantee Research Project Results

2007 Progress Report: Low Dose Effects of In Utero Exposure to Cadmium on Puberty

EPA 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 Period Covered by this Report: December 1, 2006 through November 30,2007
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

Objective:

During the last century, the onset of puberty and menarche in girls has occurred at significantly younger ages. Studies from our laboratory show that the heavy metal cadmium has potent estrogen-like activity in vitro and in vivo and that in utero exposure to environmentally relevant amounts of cadmium advances the onset of puberty, increases weight gain, and alters the development of the mammary gland in female rat offspring. This project is designed to 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.

This project has 4 objectives:

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.
Objective 2 is designed to determine the mechanism by which in utero exposure to cadmium alters the onset of puberty. Two hypotheses have been proposed for the regulation of the onset of puberty and will be tested.
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.

Progress Summary:

During the last year of funding, the in utero effects of cadmium on mammary gland development in female offspring were examined. To ask whether in utero exposure to an environmentally relevant dose of cadmium accelerates puberty onset and alters mammary gland development, pregnant animals were treated with cadmium (5 ug/kg bw) by i.p. injections on days 12 and 17 of gestation or with ethenyl estradiol (EE; 50 ug/kg bw; positive control) by daily oral gavage starting on day 12 of gestation until birth. Our published studies show that in utero exposure to cadmium mimics the in utero exposure to estradiol on puberty onset; there was an earlier vaginal opening that was not due to an increase of body weight.1 To determine whether in utero exposure to cadmium alters mammary gland development independent of its effect on puberty onset, the effects of in utero exposure on the mammary gland were assessed on postnatal days 1, 5, 10, 15, 20, 25, and 30. An unusual “blebbing” pattern was observed along the ducts of the mammary glands of 1 day old animals exposed to cadmium.

On postnatal day 5, there was a significant increase in the number of branches in the mammary gland of animals exposed in utero to cadmium (approximately 2.66 branches/unit length) compared to the number of branches in the mammary gland of control animals (approximately 1.69 branches/unit length), suggesting that in utero exposure to the metal increased the number of mammary stem and progenitor cells along the ducts and possibly altered the stem cell niche. On postnatal days 10, 15, and 20, there was a significant increase (p < 0.05) in mammary gland density in animals exposed to cadmium (39%, 43%, and 38%, respectively) compared to controls (28%, 35%, and 27%, respectively) due in part to an increase in branching providing additional evidence that in utero exposure to the metal increases the number of mammary stem and progenitor cells. The ability of in utero exposure to cadmium to expand the stem and/or progenitor cell population in the fetal mammary gland suggests that early life exposure to the metal advances the onset of puberty by accelerating the development of the gland (Tanner Stage 2) and predisposes the gland to tumorigenesis by increasing the number of putative target cells.

Future Activities:

We are currently asking whether in utero exposure to cadmium alters the expression of key developmental genes in the hypothalamus, pituitary, ovary, mammary gland, uterus, and liver. These studies are designed to define the mechanism by which in utero exposure to the metal alters mammary gland development.

Journal Articles:

No journal articles submitted with this report: View all 2 publications for this project

Supplemental Keywords:

endocrine disruptors, puberty, obesity, mammary gland development;, Health, RFA, Scientific Discipline, PHYSICAL ASPECTS, Health Risk Assessment, Physical Processes, Risk Assessments, Biology, Environmental Chemistry, Endocrine Disruptors - Human Health, endocrine disruptors, Biochemistry, Endocrine Disruptors - Environmental Exposure & Risk, Toxicology, Genetics, altered gene expression, altered sexual development, EDCs, in utero exposure, developmental biology, cadmium, endocrine disrupting chemicals, exposure, biological effects, HPG axis, human health risk, animal models, gene expression

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.