How much of an expert are you on environmental toxins and epigenetic inheritance? Practically everyone is aware of DTT. Many of us are aware of the plasticizer BPA. But how many of us are aware of vinclozolin? If you work in the field of epigenetics, you should be. The lab of Michael Skinner, at Washington State University, has been able to use this fungicide to study transgenerational epigenetic inheritance in male rat germ lines. What is it, though? In this case, after initial exposure to the environmental toxin in utero, a transgenerational epigenetic inheritance phenotype exists at least through the third generation in a lineage, in absence of that toxin. The vinclozolin rat model was applied recently in the Skinner lab’s collaboration effort, led by Dr. David Crews, a professor of psychology and zoology at the University of Texas at Austin to demonstrate a stressed behavioral phenotype.
Vinclozolin is a crop fungicide introduced in the USA in 1981. Just like DTT and BPA, Vinclozolin is an endocrine disruptor, shown to have unhealthy influences on reproduction, sexual development, and fertility in animal studies. It mimics androgens like testosterone, binding to its receptors, but not properly activating them. The Skinner lab has established that rat embryonic vinclozolin exposure by injection appears to permanently change epigenetic programming of male germ cells in males. Please see this review.
Due to improved EPA standards, updated toxicology data produced enough suspicion of Vinclozolin’s carcinogenic properties, to phase out its use for crops in the late 1990s. (Although it can still be used on commercial lawns, like golf courses.) Now, you couldn’t just wash it off apples with soap. But don’t get too worked up, because consuming environmental dose exposures has been shown NOT to cause a trangenerational epigenetic inherited phenotype, at least in rats
In the recent PNAS paper, Epigenetic Transgenerational Inheritance of Altered Stress Responses.(2012) David Crews et al. vinlozolin exposure is studied from a systems biology approach, targeting organism behavior, brain tissue metabolism, and gene expression levels. The Skinner lab collaborated with Dr David Crews at the University of Texas at Austin to observe a trangenerational epigenetic inheritance phenotype, evident only with the combination of ancestral vinlozolin exposure and stress. You might think of the vinclozolin exposure as loading the epigenotype gun, and stress as pulling the phenotype trigger.
Fair warning! I’m no B.F. Skinner, but here is the run down on the behavior experiments, for context. Rats are social animal models. For this work, adolescents were housed in pairs, always a V-L animal with control animal living together. Adolescent rats in stressed groups were exposed to “chronic restraint”. It sounds like claustrophobia type experiences, stuck inside test tubes or the like. Several behavior tests followed. Vinclozolin line or “V-L” rats swam like control rats did, in forced swim tests. In an open field test, stressed V-L rat movement comprised more of running in the outside corners of a table top, than sauntering through the centers. In the first sociability test the V-L stressed rats chose to be with a stimulus animal more than by themselves, and roamed farther and faster around their chambers. In a 2nd sociability test, the stressed V-L rats associated more with familiar/bonded rats, than with novel rats when given the choice. How is this rat behavior comparable to humans? My understanding is that these tests show that only the stressed V-L rats were anxious, seeking social familiar contact for comfort, and yet not overwhelmed / “prone to depression” by the possibility of drowning during the swim exercises.
At the tissue level, the stressed V-L rats showed a particular pattern of metabolic changes via cytochrome histochemistry in the hippocampus. Here again, if no bullets were loaded, no shots fired,…. if you whether you were a regular old stressed out rat, or nonstressed V-L rat you did not exhibit the metabolic changes in the combo rats. However, as an interesting aside, the non-stressed V-L rats were obese.
The most intriguing read in this paper was the gene expression data. Transcriptome data sets from V-L stressed rats showed the highest correlation for changes in olfactory transduction. Associations were shown between the V-L stress combo altered gene sets, and brain-specific pathways related to neurodegenerative diseases. For rats, the sense of smell is a big deal. See http://ratbehavior.org/RatOlfaction.htm Not the least of all, their sense of smell is a major regulator of rat social life, mating, mothering, etc. Interestingly, in human beings olfactory impairment is pre-symptomatic for Alzheimer’s, Huntington’s and Parkinson’s. Smelling…eating…I would think if you smell less you eat more, hence the V-L rat obesity.
Of course, we all know that in multifaceted experiments, it become more difficult to control for all the variables. Regardless the model developed here by these scientists is impressive. Can we extrapolate this stressed phenotype effect from rats to humans? Time will tell. It’ll be a rat race. (Yes, I went there.)
Crews, D., Gillette, R., Scarpino, S., Manikkam, M., Savenkova, M., & Skinner, M. (2012). Epigenetic transgenerational inheritance of altered stress responses Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1118514109