Source: UNIVERSITY OF CALIFORNIA, DAVIS submitted to
EVALUATING ENDOCRINE DISRUPTION BY PESTICIDES AND OTHER CONTAMINANTS OF THE FOOD SUPPLY
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
NEW
Funding Source
Reporting Frequency
Annual
Accession No.
1016772
Grant No.
(N/A)
Project No.
CA-D-ETX-2233-H
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Oct 1, 2018
Project End Date
Sep 30, 2023
Grant Year
(N/A)
Project Director
La Merrill, MI, .
Recipient Organization
UNIVERSITY OF CALIFORNIA, DAVIS
410 MRAK HALL
DAVIS,CA 95616-8671
Performing Department
Environmental Toxicology
Non Technical Summary
This project supports the mission of the Agricultural Experiment Station by addressing the Hatch Act area(s) of: processing, distribution, safety, marketing, and utilization of food and agricultural products.Chemicals that hurt our hormone systems are critically important hazards that represent pervasive public health problems in the United States such as infertility, obesity, diabetes, and breast cancer. For example obesity can speed up puberty, both of which can contribute to breast cancer risk. Many people are exposed to many chemicals through the food they eat, the water they drink, and the agricultural work they do. Unfortunately, most of these numerous chemicals have completely unknown effects on our health. The animals that we eat may be similarly affected which could negatively impact our food supply. This project focuses on learning more about how these chemicals may influence our hormone systems in order to lay a foundation for keeping us safe while living our daily lives.
Animal Health Component
100%
Research Effort Categories
Basic
85%
Applied
15%
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
31438401150100%
Goals / Objectives
There is a great need for high throughput assessment of endocrine disrupting activity, e.g. chemicals targeting the activity of receptors for estrogen, androgen, thyroid, and insulin. This will contribute to hazard assessment of chemicals of concern, namely those that are generated by agriculture, that have high production or waste volume, and that are found in the Californian food and drinking water supply. This project proposes to address that need. The goal of this project is two fold: 1) to develop an understanding of the endocrine disrupting properties of data-sparse chemicals in the environment (herein "chemicals of concern") and 2) to develop mechanistic insights into the hazards identified in the first goal.First, potential chemicals of concern will be screened in silico for their molecular docking to endocrine receptors. Second, candidate chemicals of concern will be examined for their dose-dependent effects on molecular and cellular receptor activities, such as receptor mediated- transcription and cell proliferation respectively. Third, a data-rich chemical of concern that was biologically active will be evaluated in vivo for endocrine disrupting effects on rodents, such as reproduction, puberty, metabolism, and mammary cancer. Lastly, molecular analyses will be conducted on chemicals of concern that produce endocrine disrupting effects on rodents to develop mechanistic insights into disease.
Project Methods
A. Evaluate molecular docking of chemicals of concern at endocrine receptorsi. Dock chemicals of concern at estrogen receptor alpha and beta, and the androgen receptor as the primary focusii. Pending successful development of docking programs, dock chemicals of concern at insulin- and thyroid hormone- receptorsB. Utilize cell-based in vitro assays to validate chemicals suspected to be EDCs based on their docking scoresi. Assess activity of chemicals of concern at endocrine receptorsa. Quantitate endocrine receptor agonism and antagonism by a subset of priority chemicals of concern (determined from agnostic docking screens) using receptor-specific luciferase assaysii. Determine whether a cellular function is impaired consistent with evidence of receptor action from abovea. Confirm disruption in estrogen and androgen receptor action by evaluating changes in receptor dependent- cellular proliferation caused by chemicals of concernb. Confirm disruption in insulin receptor action by evaluating changes in insulin-stimulated glucose uptake caused by chemicals of concernc. Confirm disruption in thyroid hormone receptor action by evaluating changes in uncoupled respiration caused by chemicals of concernd. Evaluate biological plausibility by further screen mechanistic pathways (e.g. qPCR) to further hazard characterization of toxicants with strongest dose-response and lowest threshold values.C. Conduct in vivo validation experiments exposing developing rodents to chemicals of concern identified above to ascertain the nature and degree of their endocrine disrupting effectsi. Evaluate dose-dependent pubertal and peri-pubertal metabolic outcomes in a data-rich priority chemical to anchor in silico and in vitro data to an in vivo experiment

Progress 10/01/18 to 09/30/19

Outputs
Target Audience:The target audience is the California EPA (CalEPA). Dr La Merrill gave three presentations to the CalEPA Office of Environmental Health Hazard Assessment (OEHHA) and one presentation to the CalEPA Department of Toxic Substances Control (DTSC). Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?Postdoctoral fellow Dr. Annalise vonderEmbse has conducted immunohistochemical staining and ran the analysis scripts she wrote for high content image analysis of stellate and brown adipose immunohistochemistry of adult mice (Aim 2a). She is currently working with Drs. La Merrill and Lein to revise this manuscript for publication. She identified that mice have impaired thermogenesis as early as parturition (Aim 1a), and conducted and interpreted omics analyses of this neonatal mouse tissue (Aim 1b). She is currently conducting immunohistochemical staining of these neonatal mouse tissues (Aim 2a). Integrated Genetics and Genomics Graduate student Kyle Jackson drafted two manuscripts related to brown adipose DNA methylation: in one he has identified candidate genes that persist across different ages of mice and humans (we integrated human epigenome data funded elsewhere). In the second manuscript he demonstrates persistent molecular signals in the brown adipose of young and adult mice. Pharmacology and Toxicology Graduate student Julianne Jugan has been validating various genes for their DNA methylation changes in brown adipocytes treated with DDT in vitro. She presented her research at a local retreat, of the UCSF Diabetes Center. Postdoctoral fellow Dr. Phum Tachachartvanich has been validating various genes for their DNA methylation changes in brown adipocytes treated with DDT in vitro. He has also been exploring the effects of DDT upstream of thermogenesis after treatment with DDT in vitro. All of these trainees attended weekly lab meetings where they presented their data and trouble-shot experiments. They also attended weekly journal paper reading club to learn more about the biology and methods underlying our research area. Kyle met with Dr. La Merrill weekly and attends a bimonthly oral exams practice meeting to provide further mentoring and training opportunities. How have the results been disseminated to communities of interest?Dr La Merrill gave three presentations to the CalEPA Office of Environmental Health Hazard Assessment (OEHHA) and one presentation to the CalEPA Department of Toxic Substances Control (DTSC). What do you plan to do during the next reporting period to accomplish the goals?Dr. La Merrill plans to continue to evaluate the mechanism of metabolic toxicity caused by DDT and DDE. Dr. La Merrill is also working closely with the CalEPA OEHHA to screen per- and poly- fluoroalkyl acids (PFAAs) for their endocrine disruption. There are over 7000 PFAAs and they are ubiquitously found in water supplies in the United States including California. Most of these PFAAs have not had any toxicity testing but we know they can be taken up by plants and animals and thus may adversely impact agriculture.

Impacts
What was accomplished under these goals? Our publications on the metabolic toxicity of the pesticide DDT and its persistent metabolite DDE highlight additional concerns about ongoing contamination of the California food supply by DDE and DDT. Another endocrine disruptor, tributyl tin, was used as a marine anti-foulant and can contaminant the products of the offcoast California seafood industry. We also used our androgen receptor model to screen for androgenic activity of California hydraulic fracturing chemicals. These chemicals are of concern to the CalEPA due to their potential to contaminant ground and drinking water sources. We found one chemical inhibited androgen receptor activity and this research is currently under review at a journal.

Publications

  • Type: Journal Articles Status: Published Year Published: 2019 Citation: 1. Cohn BA, Cirillo PM, La Merrill MA. Correlation of body mass index with serum DDTs predicts lower risk of breast cancer before the age of 50: prospective evidence in the Child Health and Development Studies. Journal of Exposure Science & Environmental Epidemiology, 2019, doi:10.1038/s41370-018-0072-7, PMID 30224754.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: 1. da Costa CS, Miranda-Alves L, La Merrill MA, Silva IV, Graceli JB. The tributyltin leads to obesogenic mammary gland abnormalities in adult female rats. Toxicology Letters, 2019, 307: 59-71, doi:10.1016/j.toxlet.2019.02.016.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: 1. Hu X, Li S, Cirrilo P, Krigbaum N, Tran V, Ishikawa T, La Merrill MA, Jones DP, Cohn B. Metabolome Wide Association Study of serum DDT and DDE in Pregnancy and Early Postpartum, Reproductive Toxicology, 2019, doi:10.1016/j.reprotox.2019.05.059.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: 1. Azhagiya Singam ER, Tachachartvanich P, La Merrill MA, Smith MT, Durkin KA. Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor, Journal of Physical Chemistry B, 2019, 123, 7657-7666, doi:/10.1021/acs.jpcb.9b05654.
  • Type: Journal Articles Status: Published Year Published: 2019 Citation: 1. Elmore SE, La Merrill MA*. Oxidative phosphorylation impairment by DDT and DDE, Frontiers in Endocrinology, 2019, 10:1-8, doi:10.3389/fendo.2019.00122.