There is increasing interest in differential susceptibility among humans to toxicants, as well as a growing appreciation that multiple gene variants, exposure history, and complex gene-environment interactions (GXE) are critical determinants of disease and risk. For example, individuals who carry a mutation in the glutathione S-transferase gene have far higher risk for developing Parkinson's disease when exposed to paraquat (PQ) (Goldman et al. Mov Disord 27:1652,2012). More refined animal models, in particular genetic reference families of mice, now make it practical to replicate, extend, and mechanistically validate findings from epidemiological and genetic studies of humans. In fact, Liang and colleagues validated the findings of Goldman in glutathione deficient mice (Toxicol Sci 134:366,2013). These families, including the BXD and the Collaborative Cross, provide tight experimental control, but incorporate a very high level of genetic diversity. They are ideal for mechanistic studies of GXE and can now be reliably exploited to define single gene polymorphisms, important biochemical, and molecular mechanisms of toxicity. To illustrate, we studied the neurotoxicity of PQ and MPTP in BXD recombinant inbred mouse strains. Toxicity of PQ is highly variable among these strains and covaries with PQ-related disruption of iron regulation in the midbrain. We also studied effects of MPTP on striatal dopaminergic neurotoxicity among 10 BXD lines and found that 12.5 mg/kg MPTP s.c. caused a variation of 20 - 90% in neurotoxicity as determined by reductions in dopamine and its metabolites, tyrosine hydroxylase protein and elevations in GFAP, an astrocyte marker of neurotoxicity. Furthermore, the variation in dopaminergic neurotoxicity among strains was not due to altered metabolism of MPTP to MPP+, the proximal neurotoxicant. Genetic reference panels can provide valuable information on potential genetic differences in susceptibility and GXE.
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona