Research

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We conduct research to reveal the etiology of obesity, insulin resistance, and breast cancer that aims towards prevention and treatment.

We focus our investigations on the interplay of early- life diet and chemical exposures, metabolism, and gene regulation on health and endocrine disease risk through integrated studies of people, rodents, and cells. These biological investigations are informed by in silico models utilizing machine learning and artificial intelligence approaches. We prioritize research relating to environmentally unjust chemical exposures.

We are currently investigating:

  • Chemical and epigenetic contributions to obesity and insulin resistance
  • Impaired thermogenesis resulting from changes in sympathetic tone and in brown adipocyte cell autonomous changes in gene regulation and metabolism
  • The molecular basis of how pollutants released from adipose tissue storage attenuate the benefits of bariatric surgery
  • Chemical, metabolic, and epigenetic contributions to breast/mammary cancer risk
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Exposure to DDT and other chemicals in relation to breast cancer

Elevated risk of breast cancer is associated with obesity. This initially brought La Merrill to question how chemicals stored in fat, such as DDT, contribute to obesity and breast cancer. We have examined this in the middle aged (50s) women of the Californian Child Health and Developmental Studies (CHDS) three generation birth cohort, who were exposed to DDT in the womb during the 1960s when use of DDT was commonly high. We showed a positive association between prenatal DDT exposure and four fold increased breast cancer risk in adult women. Learn more about our human study of DDT exposure in utero and breast cancer by reading the National Geographic or listening to NBC Nightly News.

We have recently worked to understand this provocative association between prenatal DDT exposure and increased breast cancer in women, both from a physical chemistry and biological research perspective. “Normally” we expect an inverse correlation of DDT with body fat mass because the excess body mass dilutes the lipophilic DDT. However, we have found in the CHDS birth cohort that this physical chemistry phenomenon is only observed in women who do not develop breast cancer. In opposition to what physical chemical properties of lipophilic DDT would predict, among women who went on to develop breast cancer, their levels of DDT were higher when their body fat was higher. One approach we have taken to investigate this observation was to evaluate and compare the total blood metabolites ‘metabolome’ across the maternal human blood collected in the 1960s as part of the CHDS with the blood of mice exposed to levels of DDT during pregnancy that mimicked the DDT levels in the CHDS maternal blood. This approach has revealed that prenatal DDT exposure perturbs the same metabolic pathways in mice and women. These pathways have been associated with both obesity and breast cancer in the work of other researchers. We are currently evaluating the mechanisms underlying the interface of metabolic changes and breast cancer risk experimentally. Listen to Dr. La Merrill’s podcast about the interaction of persistent organic pollutants and adipose tissue, with Environmental Health Perspectives.

Beyond DDT, we are evaluating chemicals prioritized for hazard assessment by the California Environmental Protection Agency. We utilize in vitro methods to test hypotheses generated by our collaborators in silico as to the molecular target of the priority chemicals, to evaluate the functional consequences, and to inform testing chemicals in vivo. This research focuses on chemicals interacting with the estrogen receptor, vitamin D receptor, and glucocorticoid signaling pathways to increase mammary cancer metastasis. A recent example, evaluating how parabens accelerate mammary tumor growth and metastasis, can be read here. Our experimental designs account for factors contributing to health disparities and environmental injustice, such as elevated exposures among different races and ethnicities, vitamin D deficiencies associated with being more melanated, and chronic psychosocial stress.

Impaired thermogenesis as a cause of obesity and insulin resistance

The current thinking on the mechanism by which pharmaceuticals (e.g. clozapine), genes (e.g. FTO), and endocrine disrupting chemicals (EDCs, e.g. DDT and DDE) contribute to obesity and diabetes is through altered regulation of calorie burning (thermogenesis). Approximately 70% of the calories we take in every day are used to keep us warm through the process of thermogenesis, which involves the mitochondria, the powerhouse of the cell. We recently reviewed research spanning over 40 years which demonstrates the pesticide DDT and its metabolite DDE are toxic to the mitochondria by inhibiting the functions of Complexes II and V of the electron transport chain, and this may alter the process of thermogenesis. Indeed we have detected RNA, protein, and lipid changes related to electron transport chain and other aspects of thermogenesis in brown adipose tissue of adult mice that had perinatal exposure to DDT, as well as brown adipocytes exposed to DDT during their differentiation. Our epigenome analyses of both human and mouse tissues suggest that epigenetic modifications are major contributors to long term signaling changes that result in the disruption of thermogenesis by DDT. We are currently studying the mechanisms of gene regulation underlying these changes, focusing on transcription factors for which DDT alters their DNA methylation. We approach this research area with various next generation sequencing, pyrosequencing, and immunoprecipitation techniques.

Overall the evidence is extremely strong that DDT and DDE are obesogens and inhibit thermogenesis, thereby causing calories to be directed towards fat deposition. We previously revealed that adult mouse insulin resistance and obesity were elevated in mice after perinatal exposure to DDT. Our ongoing research to translate our experimental toxicology evidence into humans includes demonstrating that Asian Indians immigrants (living in London or the San Francisco bay area) have very high DDT and DDE levels and that these high exposures are associated with type 2 diabetes. This is extremely concerning as the World Health Organization still recommends use of DDT for malaria control and high body burdens of DDT are found in persons living in areas currently using DDT (e.g. South Africa) or manufacturing DDT (e.g. India), and migration continues to globalize these exposures. As a result, DDE continues to be found in the majority of human samples tested. Indeed, we are currently examining levels of DDE found in teenagers with morbid obesity undergoing bariatric surgery to investigate how DDE and other lipophilic chemicals attenuate the metabolic benefits of bariatric surgery. Because the response to bariatric surgery is incredibly dynamic with many changing variables over time, we parallel this research by exposing primary human adipocytes to DDE and other lipophilic chemicals. To learn more about how these chemicals make it harder to burn calories, watch to Dr. La Merrill’s presentation on UCTV.

DDT and DDE as contributors to metabolic syndrome

We have previously shown that mice exposed to DDT and DDE developed obesity, insulin resistance, dyslipidemia, hypertension, and cardiac hypertrophy. Hence DDT and DDE contribute to risk of metabolic syndrome, which is the constellation of inter-related metabolic abnormalities in body fat, and blood- pressure, glucose, and lipids commonly observed concurrently in humans and is known to increase risk of cardiovascular disease. We have sought to extend our observations of metabolic syndrome in mice exposed to DDT and DDE to human observation studies. We evaluated DDE levels by GC/MS analytical chemistry in 1,000 elderly Swedish people who had clinical assessments of their diabetes, obesity, hypertension, and cardiac hypertrophy determined. We used an analytical technique called Structural Equation Modeling that can reveal the pathways between inter-related variables, in this case DDE and cardiometabolic health. We confirmed in humans what we observed in mice: DDE exposure was associated with increased obesity, diabetes, hypertension, and cardiac hypertrophy. When we conducted Structural Equation Modeling we found that most of the relationship between DDE and cardiac hypertrophy could be explained by the relationship between DDE and obesity, and to a lesser degree it could be explained by the relationship between DDE and hypertension. This Structural Equation Modeling approach to human observations helps us focus our laboratory research on the effect of DDT and DDE on obesity and thermogenesis to prevent heart disease. Learn more about our mouse study of DDT and metabolic syndrome in the LA Times or the London Telegraph. Learn more about our human study of DDT and hypertension in the Huffington Post.