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.

Methylmercury inhibits dopaminergic function in rat pup synaptosomes in an age-dependent manner.

Methylmercury (MeHg) is an environmental neurotoxicant that is especially harmful during brain development. Previously, we found greater sensitivity to MeHg-induced oxidative stress and greater loss of mitochondrial membrane potential in synaptosomes from early postnatal rats than in synaptosomes from older rat pups and adults. Here, we determine whether MeHg exposure also leads to greater changes in dopamine (DA) levels and dopamine transporter (DAT) function in synaptosomes from early postnatal rats. We report that MeHg exposure leads to DAT inhibition, and increases the levels of released DA compared to control; further, the effects are much greater in synaptosomes prepared from postnatal day (PND) 7 rats than in synaptosomes from PND 14 or PND 21 animals. In addition to the effects of MeHg in young rats, we observed age-dependent differences in dopaminergic function in unexposed synaptosomes: synaptosomal DA levels increased with age, whereas medium (released) DA levels were high at PND 7 and were lower in PND 14 and PND 21 synaptosomes. DAT activity increased slightly from PND 7 to PND 14 and then increased more strongly to PND 21, suggesting that higher DA release, in addition to the lower DAT activity seen in PND 7 animals, was responsible for the age differences in levels of released DA. These results demonstrate that MeHg affects the dopaminergic system during early development; it thus may contribute to the neurobehavioral effects seen in MeHg-exposed children.

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.