Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg.
We recently reported that rats exposed to PCBs and MeHg during development were impaired on the rotating rod, a test of balance and coordination that is often indicative of cerebellar damage. In addition, developmental PCB exposure is known to dramatically reduce circulating thyroid hormone concentrations, which may have a negative impact on cerebellar development. Therefore, we investigated the effects of combined PCB and MeHg exposure on Purkinje cells and the cerebellum. The serum and brains from littermates of the animals tested on the rotating rod were collected at weaning, and we also collected brains from the adult animals at the end of motor testing. Four groups were studied: 1) vehicle controls, 2) PCBs only (Aroclor 1254, 6 mg/kg/d, oral), 3) MeHg only (0.5 ppm, in dams' drinking water), and 4) PCB+MeHg (at the same doses as in individual toxicant exposures). Female Long-Evans rats were exposed beginning 4 weeks prior to breeding with an unexposed male and continuing until postnatal day (PND) 16. There was a significant reduction in serum T4 and T3 concentrations in the PCB and PCB+MeHg pups on PND21. Golgi-impregnated Purkinje cells were examined in PND21 brains, but there were no significant exposure-related effects on primary dendrite length, branching area, or structural abnormalities. However, all three male exposure groups had a marginally significant increase in Purkinje cell height, which may suggest a subtle thyromimetic effect in the cerebellum. Cresyl-violet stained sections from the adult brains showed no exposure-related effects within paramedian lobule in Purkinje cell number, total lobule volume or layer volumes (molecular, granule cell and white matter layers). Evidence is provided for the dysregulation of expression of cerebellar ryanodine receptor (RyR) isoforms in PCB-exposed brains, and this could contribute to the rotating rod deficit by changing critical aspects of intracellular calcium signaling within the cerebellum.
Roegge
Cindy S
CS
Psychiatry Department, Duke University Medical Center, Durham, NC 27710, USA. roegge@duke.edu
Morris
John R
JR
Villareal
Sherilyn
S
Wang
Victor C
VC
Powers
Brian E
BE
Klintsova
Anna Y
AY
Greenough
William T
WT
Pessah
Isaac N
IN
Schantz
Susan L
SL
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002531:Cerebellum / Q000002:abnormalities / Q000187:drug effects* / Q000473:pathology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D020262:Mercury Poisoning, Nervous System / Q000473:pathology* / Q000503:physiopathology; D008767:Methylmercury Compounds / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology* / Q000503:physiopathology; D011689:Purkinje Cells / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013963:Thyroid Hormones / Q000097:blood
D008767:Methylmercury Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D013963:Thyroid Hormones; D011078:Polychlorinated Biphenyls