Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the development of methylnitrosourea-induced mammary tumors in sprague-dawley rats.
There are concerns that early life exposure to organochlorines, including aryl hydrocarbon receptor (AhR) agonists, may lead to long-term effects and increase the risk of developing breast cancer. Our objective was to test if postnatal exposure to a mixture of 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-like chemicals would modulate the development of methylnitrosourea (MNU)-induced mammary tumors. Females received by gavage a mixture containing 3 non-ortho-polychlorinated biphenyls (PCBs), 6 polychlorinated dibenzodioxins (PCDDs), and 7 polychlorinated dibenzofurans (PCDFs), at 1, 5, 10, 15, and 20d of age. The doses were equivalent to 0, 1, 10, 100, or 1000 times the amount ingested through breast milk by a human infant during its first 24 d of life. Subgroups of 1000 x reated rats and controls were sacrificed at 21 d of age for assessment of mammary-gland development, cell death, and proliferation. Mammary-tumor development was assessed in MNU (30 mg/kg body weight ip at 50 days of age)-induced rats pre-exposed to the mixture (MNU-0, MNU-1, MNU-10, MNU-100, MNU-1000). Rats were sacrificed when their mammary tumors reached 1 cm in diameter, or when the rats reached > or = 32 wk of age. Mammary-gland whole mounts were analyzed with all palpable and microscopic lesions (n = 1563) histologically classified and grouped as benign, intraductal proliferations, or malignant. There were no marked effects on age at onset of puberty (vaginal opening) and estrous cyclicity. Despite a significant decrease in proliferating cell nuclear antigen (PCNA)-positive mammary cells in 1000 x treated 21-d-old rats, there were no long-term dose-response effects on mammary-gland morphology and tumor development. In conclusion, postnatal exposure to the mixture of AhR agonists had no significant effects on the development of MNU-initiated mammary tumors.
Desaulniers
Daniel
D
Environmental and Occupational Toxicology Division, Health CanadaOttawa, Ontario, Canada. daniel_desaulniers@hc-sc.gc.ca
Leingartner
Karen
K
Musicki
Biljana
B
Cole
Jonathan
J
Li
Ming
M
Charbonneau
Michel
M
Tsang
Benjamin K
BK
D000367:Age Factors; D000477:Alkylating Agents; D000818:Animals; D000831:Animals, Newborn; D001572:Benzofurans / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D000072338:Dibenzofurans, Polychlorinated; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004781:Environmental Exposure / Q000009:adverse effects* / Q000032:analysis; D004785:Environmental Pollutants / Q000633:toxicity*; D030762:Estrous Cycle / Q000187:drug effects; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008770:Methylnitrosourea; D008892:Milk / Q000009:adverse effects / Q000737:chemistry; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D012307:Risk Factors
D000477:Alkylating Agents; D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018809:Proliferating Cell Nuclear Antigen; D018336:Receptors, Aryl Hydrocarbon; D008770:Methylnitrosourea; D011078:Polychlorinated Biphenyls