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Mitochondrial transduction of ocular teratogenesis during methylmercury exposure
Michael F O'Hara1, Jeffrey H Charlap, Robert C Craig
1Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
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.
Conclusion:
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.
Insights
Methylmercury (MeHg) causes developmental toxicity by inhibiting mitochondrial 16S ribosomal RNA (16S rRNA) expression. PK11195, a ligand for the mitochondrial peripheral-type benzodiazepine receptor (Bzrp), rescues these effects and reduces malformations in MeHg-exposed embryos.
Area of Science:
- Developmental toxicology
- Mitochondrial biology
- Pharmacology
Background:
- Methylmercury (MeHg) is a potent neurotoxin with known developmental toxicity.
- Mitochondrial dysfunction is implicated in various toxicological processes.
- The mitochondrial peripheral-type benzodiazepine receptor (Bzrp) is involved in cellular stress responses.
Purpose of the Study:
- To investigate the correlation between MeHg developmental toxicity and mitochondrial 16S ribosomal RNA (16S rRNA) expression.
- To evaluate the protective effects of PK11195, a Bzrp ligand, against MeHg-induced developmental toxicity.
Main Methods:
- Pregnant CD-1 mice were exposed to MeHg with or without PK11195 on Day 9 of gestation.
- Fetuses were analyzed using RT-PCR, histology, and teratology on Days 9, 15, and 17.
- Embryo cultures were used to assess the effects of Hg(II) and 5-aminolevulinic acid (ALA).
Main Results:
- MeHg exposure induced significant teratogenic effects, including microcephaly, microphthalmia, and cleft palate.
- PK11195 co-treatment significantly reduced the incidence of these malformations, demonstrating a rescue effect.
- MeHg exposure inhibited 16S rRNA expression in the embryonic forebrain, an effect reversed by PK11195.
- ALA addition enhanced Protoporphyrin-IX (PP9) levels in a PK11195-sensitive manner, suggesting a link to heme biosynthesis.
Conclusions:
- MeHg-induced teratogenicity is partly linked to late steps in the heme biosynthesis pathway via the Bzrp.
- PK11195 acts as a protective agent, mitigating the developmental toxicity of mercury in embryos.
- Targeting mitochondrial pathways offers a potential therapeutic strategy against heavy metal developmental toxicity.