Developmental coexposure to polychlorinated biphenyls and polybrominated diphenyl ethers has additive effects on circulating thyroxine levels in rats.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants found in seafood and dairy products. PCBs and PBDEs are structurally similar chemicals and affect thyroid hormone function and behavior in children and laboratory rodents. Although coexposure frequently exists, the in vivo developmental effects of combined exposure to PCBs and PBDEs on thyroxine (T4) levels are unknown. We examined the effects of PCB and PBDE coexposure from gestational day 6 through postnatal day (p) 21, alone and in combination, on T4 levels in rat offspring. In males, exposure to PCBs and PBDEs at 1.7, 5, 10, 20, 40, and 60 µmol/kg/day induced equivalent and dose-dependent reductions in T4 from p 7 to p 21. Exposure to equimolar mixtures of PCBs and PBDEs at 3.4, 10, 20, 40, and 80 µmol/kg/day additively reduced T4 from p 7 to p 21 in males. In a second series of experiments, we determined sex effects on the mixture exposures and found that coexposure to PCBs and PBDEs had similar additive effects on T4 levels in male and female offspring. This study demonstrates that equimolar exposure to PCBs and PBDEs induces similar reductions in T4 levels and that coexposure to a mixture of PCBs and PBDEs has additive effects on T4 levels. These thyroid hormone effects of coexposure to PCBs and PBDEs are important when considering the cumulative effects of coexposure to multiple environmental thyroid hormone-disrupting agents in risk assessment for developmental disorders.

Polychlorinated biphenyls and polybrominated diphenyl ethers alter striatal dopamine neurochemistry in synaptosomes from developing rats in an additive manner.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with changes in behavior and neurochemical function in laboratory animals and behavioral deficits in children. PCBs and PBDEs are found in food, especially in seafood and dairy products, and coexposure to these contaminants is likely. We examined the effects of an environmentally relevant mixture of PCBs (Fox River Mix [FRM]) and a PBDE mixture (DE-71) alone and in combination on synaptosomal and medium dopamine (DA) levels and the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in striatal synaptosomes derived from postnatal days (PND) 7, PND14, or PND21 rats. FRM elevated medium DA and reduced synaptosomal DA concentrations with greater potency than equimolar concentrations of DE-71. The effects of FRM, but not DE-71, were dependent on the age of the animals from which the synaptosomes were derived, with greater effects observed in synaptosomes from the youngest animals. We used Bliss' model of independence to assess the possible interaction(s) of a 1:1 mixture of FRM and DE-71 on synaptosomal DA function and found that the effects of the FRM/DE-71 mixture were additive. Furthermore, as for FRM alone, the effects of the FRM/DE71 mixture were greater in synaptosomes prepared from PND7 rats than in synaptosomes from PND14 and PND21 rats. Because the effects of these contaminants are additive, it is necessary to take into account the cumulative exposure to organohalogen contaminants such as PCBs and PBDEs during risk assessment.

Delayed spatial alternation impairments in adult rats following dietary n-6 deficiency during development.

Dietary n-3 fatty acid (FA) deficiencies during development can cause learning and memory impairments, but the functional effects of dietary n-6 FA deficiencies, reflected in a lowered n-6/n-3 ratio, are less clear. We investigated the effects of maternal diets containing fish oils, resulting in lowered n-6/n-3 ratios, on a spatial working memory task in their offspring. Starting on gestational day 6, Sprague-Dawley timed-pregnant rats were placed on one of three experimental diets: control (unadulterated powdered rat chow), Pacific Ocean (PO) fish (powdered rat chow containing 20% (w/w) lyophilized PO salmon), or PO oil (powdered rat chow containing 6% (w/w) oil extracted from PO salmon). The 6% oil dose was selected because it is equivalent to the amount of oil in the 20% lyophilized fish diet. The experimental diets were fed until weaning on postnatal day (PND) 21, at which time all pups were placed on the rat chow diet. Starting on approximately PND77, one male and one female from each litter began a cognitive test battery using 2-lever operant chambers. PO groups failed to reach the same level of performance as the controls on the delayed spatial alternation (DSA) task and also showed decreased performance on delay trials. FA analyses of the diets found that the n-6/n-3 ratios for the PO fish and oil groups were reduced to 2.5 and 3.2, respectively, vs. 6.9 for controls. Analysis of brain tissue taken from pups on PND21 confirmed that the n-6/n-3 ratios within the brain were significantly reduced from 1.18 for controls to 0.87 and 0.90 for PO fish and oil groups, respectively. Specifically, the PO diets significantly increased long-chain n-3 FAs (20:5 n-3 and 22:6 n-3) and decreased long-chain n-6 FAs (20:4 n-6 and 22:4 n-6) in the brain. Thus, the observed delayed spatial alternation impairments in rats fed PO fish and fish oil are hypothesized to have resulted from the altered n-6/n-3 FA ratios.

Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: implications for developmental neurotoxicity.

We show that developmental exposure of the laboratory rat to the coplanar polychlorinated biphenyl (PCB) congener 3,4,3',4'-tetrachlorobiphenyl (TCB) and the structurally similar congener 3,4,5,3',4'-pentachlorobiphenyl (PtCB) elevates dopamine (DA) concentrations in the prefrontal cortex (PFC). To determine whether these coplanar congeners are estrogenic, and may thus contribute to the elevations in PFC DA, we measured uterine wet weight (UWW) in prepubertal rats exposed to TCB or PtCB. For comparison, additional animals were exposed to either the ortho-substituted congener 2,4,2',4'-tetrachlorobiphenyl (o-TCB) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), a coplanar congener highly resistant to metabolism. Both TCB and PtCB increased UWW, but this effect was blocked after exposure to the anti-estrogen ICI 182,780. Neither o-TCB nor HCB altered UWW. These results demonstrate that certain coplanar PCB congeners and/or their metabolites, are estrogenic, and suggest that exposure during critical periods of neuronal development may increase central DA concentrations, and by inference, alter behavior.

Polychlorinated biphenyls alter extraneuronal but not tissue dopamine concentrations in adult rat striatum: an in vivo microdialysis study.

Polychlorinated biphenyls (PCBs) reduce tissue dopamine (DA) concentrations and increase media DA concentrations in both in vitro preparations of bovine adrenal chromaffin cells and adult rat striatal tissue. To determine whether these changes also occur in the intact animal, we used in vivo microdialysis to determine changes in concentrations of DA in striatal dialysates from freely moving adult male rats after exposure to 25 mg/kg/day Aroclor 1254 for varying periods of time. We also determined DA concentrations in striatal tissue obtained postmortem from similarly treated animals. The effects of PCBs on dialysate DA concentrations depended on the length of exposure; DA concentrations were significantly elevated after 3 days of exposure and were significantly reduced after exposure for periods of 1 week or longer. On the other hand, striatal tissue concentrations of DA, determined postmortem in rats exposed to PCBs for the same periods of time, were not significantly altered. We suggest that these time-dependent alterations in dialysate DA concentrations a) reflect PCB-induced alterations of both plasma membrane and vesicular DA transporter function; b) provide a more sensitive index of altered central DA function after exposure to PCBs than does measurement of postmortem tissue DA concentrations; and c) play an important role in mediating some PCB-mediated changes in behavior.