title: Toxicological effects of gestational and lactational exposure to a mixture of persistent organochlorines in rats: systemic effects.
abstract: A large multi-disciplinary study was conducted to investigate the systemic, neurodevelopmental, neurochemical, endocrine, and molecular pathological effects of a mixture of reconstituted persistent organochlorine pollutants (POP) based on the blood profiles of Canadians residing in the Great Lakes/St. Lawrence region. This report outlines the overall study design and describes the systemic effects in rat offspring perinatally exposed to the POP mixture. Maternal rats were administered orally 0, 0.013, 0.13, 1.3, or 13 mg/kg bw/day of the mixture from gestational day (GD) 1 to postnatal day (PND) 23. Positive and negative controls were given Aroclor 1254 (15 mg/kg bw/day) and corn oil (vehicle), respectively. The rat pups were reared, culled to 8 per litter, and killed on postnatal days 35, 70, and 350, at which time tissues were collected for analysis. Exposure to high doses of the mixture elicited clinical, biochemical, and pathological changes and high mortality rates in rat offspring. Aroclor 1254 produced similar effects but a lower mortality than was seen in POP mixture groups. Biochemical changes consisted of increased liver microsomal activities and elevated serum cholesterol. Hepatomegaly was observed in the highest dose group of the mixture and in the positive control. Liver, thymus, and spleen were the target organs of action. Microscopic changes in the liver consisted of vacuolation and hypertrophy, and those in the thymus were characterized by reduced cortical and medullary volume. The spleen showed a treatment-related reduction in lymphocyte density and lymphoid areas. This study demonstrates that exposure to the POP mixture up to 13 mg/kg/day perinatally produced growth suppression, elevated serum cholesterol, increased liver microsomal enzyme activities, and immunopathological changes in the thymus and spleen, and lethality. Most of the effects were seen at dose levels much higher than expected human exposure.
authors.affiliation: Environmental and Occupational Toxicology Division, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario. lh_chu@hc.sc.gc.ca
authors.forename: Ih
authors.initials: I
authors.lastname: Chu
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Bowers
authors.forename: Don
authors.initials: D
authors.lastname: Caldwell
authors.forename: Jamie
authors.initials: J
authors.lastname: Nakai
authors.forename: Olga
authors.initials: O
authors.lastname: Pulido
authors.forename: Al
authors.initials: A
authors.lastname: Yagminas
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wade
authors.forename: David
authors.initials: D
authors.lastname: Moir
authors.forename: Santokh
authors.initials: S
authors.lastname: Gill
authors.forename: Rudi
authors.initials: R
authors.lastname: Mueller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002170:Canada; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005506:Food Contamination / Q000032:analysis; D006529:Hepatomegaly / Q000139:chemically induced / Q000473:pathology; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D007774:Lactation / Q000187:drug effects*; D008136:Longevity / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D006843:Hydrocarbons, Chlorinated; D014874:Water Pollutants, Chemical; D002784:Cholesterol