| Summary: | Cycad consumption remains one of the strongest etiological factors in the epidemiology of amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC). Two water insoluble steryl glucosides (stigmasterol β-D-glucoside (SG), and β-sitosterol β-D-glucoside (BSSG)) identified in washed cycad have previously been demonstrated to have neurotoxic effects in both in vitro and in vivo studies. The present study aims to address the variations in age of onset and rate of disease progression, by examining the hypothesis that factors contributing to adult onset diseases may first arise during fetal development. We studied the impact of a prenatal and secondary adult re-exposure to a combination of BSSG and SG on disease onset and progression, and also investigated possible sex differences in disease outcomes. Pregnant CD-1 mice were fed a combination of 0.6mg BSSG and 0.4mg SG on embryonic days 10-11, to target the differentiation of the substantia nigra; other pregnant females received the control diet. Pups were weighed within 24hr of birth, and weekly thereafter. Animals were monitored behaviorally using a series of tests starting at 5 weeks for the duration of the study. At 18 weeks, subsets of both litters were exposed to dietary BSSG and SG in the same doses as before for 15 weeks. Afterwards, animals were perfused and CNS tissue was examined for associated neuropathologies. Behavioral and neuropathological assessments revealed significant differences in the response of adult male and female mice to BSSG and SG exposure. While male mice exposed to BSSG and SG during gestation showed significant weight increases and behavioral deficits irrespective of whether or not they received a secondary exposure, female mice showed marked hyperactivity only if they received BSSG and SG as adults. BSSG and SG exposure also induced significantly decreased tyrosine hydroxylase (TH) labeling in the nigro-striatal pathway, increased apoptosis and gliosis, and resulted in widespread lipid accumulation in male mice; these effects were not observed in female mice. This study demonstrates that developmental exposure to cycad neurotoxins triggers an insult that may elicit a dominant phenotype based on the period of exposure, and that the insult is exacerbated by a secondary exposure, depending on animal sex.
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