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ALTERED MAMMARY GLAND DEVELOPMENT IN MALE RATS EXPOSED TO GENISTEIN AND METHOXYCHLOR
Citation:
WANG, X., E. BARTOLUCCI-PAGE, S. E. FENTON, AND L. YOU. ALTERED MAMMARY GLAND DEVELOPMENT IN MALE RATS EXPOSED TO GENISTEIN AND METHOXYCHLOR. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 91(1):93-103, (2006).
Impact/Purpose:
To evaluate mammary responses to genistein and methoxychlor and investigate relevant mechanisms of toxicity
Description:
Genistein is a prevalent phytoestrogen whose presence in human and animal foods may affect biological actions of synthetic endocrine active compounds. We have previously reported that in utero and lactational exposure to genistein and the endocrine active pesticide methoxychlor caused mammary epithelial proliferation in 21-day old male rats; combined exposure to the two compounds resulted in significant feminization of the male mammary glands. The goals of the current study were to evaluate mammary responses to genistein and methoxychlor at the peripubertal and adult stages and investigate relevant mechanisms. Following in utero and lactation exposure (dosing through maternal diet) and direct dietary exposure, the inguinal mammary gland of male rats (90 days of age) exhibited significant morphological alterations in the groups treated with genistein and/or methoxychlor compared to the control. Genistein exposure (at both 300 and 800 ppm dietary) caused alveolar epithelial hyperplasia, whereas methoxychlor exposure (800 ppm) led to alveolar enlargement and ductal elongation. Combining the two compounds caused prominent hyperplasia in both ductules and alveoli; secretory material was also seen in readily recognizable alveolar lumens, which are absent in untreated males. In a separate experiment, similar morphological changes were observed in 42-day old male rats gavage-dosed from day 32 to 41 with genistein (100 mg/kg/day), methoxychlor (25 mg/kg/day), or their combination. Results of this peripubertal experiment indicated that the proliferative response and feminization can result from short exposure during postnatal mammary development. A survey of gene expression in the mammary tissue using a cDNA microarray and an evaluation of specific protein factors relevant to mammary growth indicated that the observed male mammary effects are likely due to interactions between steroid hormone receptor-mediated signals and growth factor-driven cellular pathways. The distinctive responses associated with the genistein-methoxychlor combination were likely linked to enhanced actions of insulin-like growth factor 1 and Wnt signaling pathways. The precise mechanisms of genistein-methoxychlor interactions and the implications for long-term mammary development and disease-susceptibility require further investigation.
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ALTERED MAMMARY GLAND DEVELOPMENT IN MALE RATS EXPOSED TO GENISTEIN AND METHOXYCHLOR