Mitochondrial transduction of ocular teratogenesis during methylmercury exposure.
BACKGROUND
The purpose of the present study was to investigate the correlation between MeHg developmental toxicity and mitochondrial 16S ribosomal RNA (16S rRNA) expression in the embryonic forebrain and pharmacological intervention with PK11195, a ligand for the mitochondrial peripheral-type benzodiazepine receptor (Bzrp).


METHODS
Pregnant CD-1 mice were dosed with methylmercury (II) chloride (MeHg) with or without 4 mg/kg PK11195 on Day 9 of gestation. Fetuses were examined on Day 9 (RT-PCR), Day 15 (histology), and Day 17 (teratology).


RESULTS
MeHg (10 mg/kg) induced microcephaly, microphthalmia and cleft palate. The mean incidences of malformed fetuses were 47.7% with MeHg (P < 0.001) and 19.2% with PK11195 co-treatment (P < 0.01 for rescue). Cleft palates were 12.8% and 1.5%, respectively. An estimate of neurocranial circumference revealed a small (5%) but highly significant (P < 0.001) reduction that was rescued in a subset of co-treated fetuses (P < 0.05). RT-PCR analysis of the Day 9 forebrain revealed inhibition of 16S rRNA expression 3.0 hr after 5 mg/kg MeHg exposure (P < 0.001). This effect was rescued with PK11195 (P < 0.001). Preliminary findings revealed a similar response-rescue in cultured embryos exposed to 1 microM Hg(II) when exogenous 5-aminolevulinic acid (ALA) was added. Protoporphyrin-IX (PP9), the penultimate precursor to heme and an endogenous ligand of the Bzrp, increased in a manner that was ALA-dependent and PK11195-sensitive.


CONCLUSIONS
At least some teratological effects of Hg appear linked with late steps in the heme biosynthesis pathway through the Bzrp. PK11195, a ligand for these mitochondrial receptors, significantly lessens the risk of microphthalmia, microcephaly, and cleft palate in Hg-poisoned embryos.
O'Hara
Michael F
MF
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Charlap
Jeffrey H
JH
Craig
Robert C
RC
Knudsen
Thomas B
TB
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000235:genetics*; D000818:Animals; D005124:Eye Abnormalities / Q000139:chemically induced* / Q000196:embryology; D005260:Female; D008627:Mercuric Chloride / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000235:genetics*; D011247:Pregnancy; D016548:Prosencephalon / Q000002:abnormalities / Q000196:embryology; D012336:RNA, Ribosomal, 16S / Q000235:genetics*
D008767:Methylmercury Compounds; D012336:RNA, Ribosomal, 16S; D008627:Mercuric Chloride