Agricultural and Forestry Worker Health Risks from Pesticides: Evaluation of Global Impact, Epigenetic Effects and Synergism Directly on Human Systems

The US Department of Labor Statistics report that agriculture is one of the most dangerous occupations in the country. If chronic health conditions are included in this analysis, the threat is even greater. Exposure to agrochemicals, the use of pesticides for personal protection, and exposure to mixtures of these chemicals in farming and forestry are among the occupational hazards of greatest concern. Better information is needed on human health risk to chemicals in these occupations, and the US National Academy of Sciences has recognized the need for using human (not animal) models. Experimental techniques are now available to examine global molecular impacts of agrochemicals on human systems, and the recent discovery of long non coding RNAs in human epigenetics has never been considered relative to chemical exposure and risk analysis to environmental chemicals. Our goal is to change these paradigms, focusing on chemistries where human exposure and potential multiple chemical exposure to farmers and foresters are highest, with pesticides like DEET, fipronil and permethrin (as model chemicals). We present preliminary data that the exposure of primary human hepatocytes to low levels of DEET (a popular insect repellent) and examination of global gene expression (using RNAseq) broadly disrupts male and female steroid hormone synthesis, affects at least one breast cancer gene, and mostly down regulates long non-coding RNAs. The aim of this proposal is to compare these data to that of fipronil (commonly used in urban applications and on animals), to examine potential syngergism related to risk analysis, and to provide the first studies of the impact of environmental chemicals and mechanisms of action of these chemistries at the epigenetic level involving long non-coding RNAs and micro RNAs.

OUTCOMES: A graduate student working on this project earned 1st place in the 11th Annual North Carolina State University Graduate Research Symposium. His work is very timely because he is studying the impact of DEET and other urban chemicals on global gene expression in primary female human hepatocytes to obtain leads on potential human health risks. The system that he has developed allows us to now examine rapidly the potential health risks of the repeated use of repellents like DEET but also chemical mixtures and potentially develop a blood test for exposure to these compounds. DEET has been the gold standard for mosquito repellents for over 50 years and has an excellent safety record. The need for the repeated use of repellents like DEET for potentially extended periods on pregnant women and women during their child bearing years and potentially for protection from Zika is one important interest of the laboratory. This information is also potentially of importance to worker safety in professions like Agriculture and Forestry in our state and country (where repellents are used for insect and tick protection), to military personnel, and for the public at large in North

Carolina. His research is published in two peer reviewed publications:

Mitchell III, R. D., A. Dhammi, A. Wallace, E. Hodgson and R. M. Roe. 2016. Impact of environmental chemicals on the transcriptome of primary human hepatocytes: potential for health effects. J. Biochem. Mol. Tox. 30:375-395.

Mitchell III, R.D., Wallace, A., Hodgson, E., Roe, RM. (2017) Differential Expression Profile of lncRNAs from Primary Human Hepatocytes Following DEET and Fipronil Exposure. Int J Mol Sci. 2017 Oct; 18(10): 2104. Published online 2017 Oct 7. doi: 10.3390/ijms18102104

The senior author on these two papers, Robert Mitchell, was successful in obtaining his Ph.D. in entomology Spring 2017 with this work, is now a postdoc in my lab and interning part time with USDA APHIS. A second new student that started his M.S. degree work in August of 2017 on a degree in Toxicology is working on another aspect of these studies.

Robert’s work was featured in a NC State Student Spotlight.

https://cals.ncsu.edu/news/student-spotlight-mitchell-studies-how-repell... expression-in-human-liver/

Note: A graduate student working on this project earned 1st place in the 11th Annual North Carolina State University Graduate Research Symposium. His work is very timely because he is studying the impact of DEET and other urban chemicals on global gene expression in primary female human hepatocytes to obtain leads on potential human health risks. The system that he has developed allows us to now examine rapidly the potential health risks of the repeated use of repellents like DEET but also chemical mixtures and potentially develop a blood test for exposure to these compounds. DEET has been the gold standard for mosquito repellents for over 50 years and has an excellent safety record. The need for the repeated use of repellents like DEET for potentially extended periods on pregnant women and women during their child bearing years and potentially for protection from Zika is one important interest of the laboratory. This information is also potentially of importance to worker safety in professions like Agriculture and Forestry in our state and country (where repellents are used for insect and tick protection), to military personnel, and for the public at large in North Carolina. His research is in press in the Journal of Biochemical and Molecular Toxicology.