In utero and lactational exposure to a mixture of environmental contaminants detected in Canadian Arctic human populations alters retinoid levels in rat offspring with low margins of exposure.

Arctic inhabitants are highly exposed to persistent organic pollutants (POP), which may produce adverse health effects. This study characterized alterations in tissue retinoid (vitamin A) levels in rat offspring and their dams following in utero and lactational exposure to the Northern Contaminant Mixture (NCM), a mixture of 27 contaminants including polychlorinated biphenyls (PCB), organochlorine (OC) pesticides, and methylmercury (MeHg), present in maternal blood of the Canadian Arctic Inuit population. Further, effect levels for retinoid system alterations and other endpoints were compared to the Arctic Inuit population exposure and their interrelationships were assessed. Sprague-Dawley rat dams were dosed with NCM from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were obtained from offspring on PND35, PND77, and PND350 and their dams on PND30 for analysis of tissue retinoid levels, hepatic cytochrome P-450 (CYP) enzymes, and serum thyroid hormones. Benchmark doses were established for all endpoints, and a partial least-squares regression analysis was performed for NCM treatment, hepatic retinoid levels, CYP enzyme induction, and thyroid hormone levels, as well as body and liver weights. Hepatic retinoid levels were sensitive endpoints, with the most pronounced effects at PND35 though still apparent at PND350. The effects on tissue retinoid levels and changes in CYP enzyme activities, body and liver weights, and thyroid hormone levels were associated and likely driven by dioxin-like compounds in the mixture. Low margins of exposure were observed for all retinoid endpoints at PND35. These findings are important for health risk assessment of Canadian Arctic populations and further support the use of retinoid system analyses in testing of endocrine-system-modulating compounds.

Effects of environmentally relevant mixtures of persistent organic pollutants on the developmental neurobiology in rats.

We report the developmental neuropathology for rat pups at postnatal day (PND) 37 and PND 77 and the molecular biomarkers for PND 35, 75, and 350 after perinatal exposure to a reconstituted mixture of persistent organochlorine pollutants (POPs) based on the blood profiles of people living in the Great Lake Basin. The developmental neuropathology included routine histopathology evaluation, quantification of cell proliferation and death in the subventricular zone, linear morphometric measurements, and transcriptional analysis. No histopathological, structural, or stereological changes were observed in animals treated with the POPs or Aroclor 1254, on PND 37 or PND 77. While no transcriptional changes were found in Arcolor-treated animals, significant transcriptional changes were observed on PND 350 in female offspring perinatally exposed to 0.13 mg/kg of the POP mixture. Markers of the cholinergic system including acetylcholinesterase and the muscarinic receptors (subtypes M1-M5) were downregulated 2- to 6-fold. In addition, structural genes including neurofilaments (NFLs) and microtubule-associated protein (MAP-2) were downregulated at least 2-fold or greater. Our results support that in utero and lactational exposure to the chemical mixture of POPs lead to developmental changes in adult rat brains.

Early developmental neurotoxicity of a PCB/organochlorine mixture in rodents after gestational and lactational exposure.

The developmental and neurobehavioral effects of gestational and lactational exposure to a mixture of 14 polychlorinated biphenyls (PCBs) and 11 organochlorine pesticides was examined and compared against the commercial PCB mixture Aroclor 1254. The mixture was based on blood levels reported in Canadian populations living in the Great Lakes/St. Lawrence basin. Pregnant Sprague-Dawley rats were dosed orally with 0.013, 0.13, 1.3, or 13 mg/kg of the chemical mixture or 15 mg/kg of Aroclor 1254 from gestation day (GD) 1 to postnatal day (PND) 23. The highest mixture dose decreased maternal gestation and lactation body weight, and produced high mortality rates (80% overall) and reductions in offspring weight that persisted to adulthood. Aroclor 1254 produced smaller but persistent decreases in offspring weight without affecting maternal weight or offspring mortality. Aroclor 1254 and 13 mg/kg of the mixture produced comparable decreases in maternal and offspring serum T4 levels and comparable alterations to maternal thyroid morphology. Aroclor 1254 delayed the righting reflex and ear opening, accelerated eye opening, and reduced grip strength at PNDs 10-14. The mixture at 13 mg/kg delayed negative geotaxis in addition to delaying righting reflex and ear opening and reducing grip strength but had no effect on eye opening. Lower mixture doses (0.13 and 1.3 mg/kg) also delayed ear opening but affected no other parameters. Developmental exposure to the chemical mixture was found to be more toxic than exposure to Aroclor 1254 and produced a different profile of effects on early neurodevelopment. This PCB/organochlorine pesticide mixture affects mortality, growth, thyroid function, and neurobehavioral development in rodents.

Gestational and lactational exposure to the polychlorinated biphenyl mixture Aroclor 1254 modulates retinoid homeostasis in rat offspring.

Polychlorinated biphenyls (PCBs) induce a broad spectrum of biochemical and toxic effects in mammals including alterations of the vital retinoid (vitamin A) system. The aim of this study was to characterize alterations of tissue retinoid levels in rat offspring and their dams following gestational and lactational exposure to the PCB mixture Aroclor 1254 (A1254) and to assess the interrelationship of these changes with other established sensitive biochemical and toxicological endpoints. Sprague-Dawley rat dams were exposed orally to 0 or 15 mg/kg body weight/day of A1254 from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were collected from the offspring on PNDs 35, 77 and 350. Tissue and serum retinoid levels, hepatic cytochrome P450 (CYP) enzymes and serum thyroid hormones were analyzed. A multivariate regression between A1254 treatment, hepatic retinoid levels, hepatic CYP enzymes activities, thyroid hormone levels and body/liver weights was performed using an orthogonal partial least-squares (PLS) analysis. The contribution of dioxin-like (DL) components of A1254 to the observed effects was also estimated using the toxic equivalency (TEQ) concept. In both male and female offspring short-term alterations in tissue retinoid levels occurred at PND35, i.e. decreased levels of hepatic retinol and retinoic acid (RA) metabolite 9-cis-4-oxo-13,14-dihydro-RA with concurrent increases in hepatic and renal all-trans-RA levels. Long-term changes consisted of decreased hepatic retinyl palmitate and increased renal retinol levels that were apparent until PND350. Retinoid system alterations were associated with altered CYP enzyme activities and serum thyroid hormone levels as well as body and liver weights in both offspring and dams. The estimated DL activity was within an order of magnitude of the theoretical TEQ for different endpoints, indicating significant involvement of DL congeners in the observed effects. This study shows that tissue retinoid levels are affected both short- and long-term by developmental A1254 exposure and are associated with alterations of other established endpoints of toxicological concern.

Effect of anaesthetics[sol ]terminal procedures on neurotransmitters from non-dosed and aroclor 1254-dosed rats.

Subtle effects of low-dose exposure to environmental toxicants may be altered or masked by an inappropriate choice of anaesthesia prior to manipulation or termination of experimental animals. This study was designed to investigate effects of various anaesthetics and terminal procedures on neurotransmitters from male Sprague-Dawley rats. Significant changes in neurotransmitters were observed in the caudate nucleus, nucleus accumbens, hippocampus and substantia nigra but not the frontal cortex upon exposure to isoflurane, an Equithesin-like mixture or carbon dioxide relative to control animals that were decapitated without anaesthesia. Terminal use of any of these three anaesthetics also masked or altered some of the changes induced by exposure to Aroclor 1254. These results suggest that it is critical to avoid anaesthetizing experimental animals and that decapitation is the preferred method for euthanasia when conducting neurochemical studies.