MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains

Abstract

Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5 mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

“…The accessibility of comprehensive genetic information regarding different strains of mice and mouse genome have provided researchers with unique opportunities to study the role of genetic predisposition in response to an insult. Quantitative Trait Loci (QTL) analyses have been performed to pinpoint candidate genes that may be involved in response variation regarding multiple neurotoxicants including MPTP and paraquat [38, 40]. Thus, similar analyses in the OF1 mice may provide unique insight into the mechanisms of MPTP, and perhaps PD, susceptibility, if indeed they are shown to lose DA neurons to very low doses of MPTP.…”

Sex Differences in Neurotoxicogenetics

“…Although, both sexes presented highly similar responses to MPTP insult, they found some differences, notably in the production of GFAP, a marker of astrocyte activation. Mapping of the index for dopamine damage in the striatum yielded the same QTL on chromosome 1 at 60 Mb ( Alam et al, 2016 ).…”

Paraquat Toxicogenetics: Strain-Related Reduction of Tyrosine Hydroxylase Staining in Substantia Nigra in Mice

“…Future work will involve at least 30 strains and both sexes. Thirty strains are minimal for identification of candidate genes that underlie individual differences in sensitivity, and the inclusion of both sexes is necessary because in some toxicological studies, we observe similarities and important sex differences ( Alam et al, 2016 ). Finally, it is important to note that while we assert strain differences in PQ effects on TH staining, we did not observe a significant strain × treatment interaction by ANOVA.…”