UC Santa Cruz

Metabolic diseases, such as obesity or type 2 diabetes, are affecting millions of individuals globally and are projected to continue impacting sixty percent of the world’s population by 2050. Factors attributed to the development of metabolic diseases have often been identified as sedentary lifestyle and hypercaloric diets. In recent years the idea of the “exposome,” or the sum of an individual’s environmental exposures within their lifetime, has shed light on the importance of chemical exposure and incidence of metabolic disease. One environmental factor that can perturb metabolic function is the use of tobacco products. Specifically, exposure to nicotine can elicit metabolic disruption from direct, in utero, and ancestral exposures. Though global tobacco use rates among adults have declined, there are still communities that continue to use tobacco like adult men. Paternal smoking has also been associated with childhood overweight and obesity status in descendants and grandchildren. Paternal nicotine use has been shown to increase incidence of metabolic disruption in the next generation of male mice. However, further characterization of paternal nicotine exposure and metabolic outcomes in the next generation remains to be characterized. Investigation into the metabolic outcomes upon paternal nicotine exposure in females of the next generation remains to be elucidated. Also, investigation into dietary interventions upon paternal predisposition to nicotine exposure has not been previously explored. Referring to the idea of the exposome, we are exposed to multiple factors within our lifetime. It is important to understand the metabolic outcomes that arise upon paternal nicotine exposure and dietary intervention with a hypercaloric diet as we are exposed to multiple factors within ours and our ancestors’ lifetime. It is also important to understand the metabolic outcomes of direct exposure to nicotine. Direct nicotine exposure in the F0 generation has been associated with increased risk of metabolic disruption in the form of metabolic syndrome. Here we characterize the metabolic outcomes upon direct or ancestral exposure to nicotine in a rodent model. In Chapter 1 of this dissertation, I thoroughly detail relevant information on various fields that mesh into my novel research topic. Specifically, I outline the recent prevalence and projections of metabolic syndrome and its associated disorders at the global level. I discuss the factors that are associated with the development of metabolic diseases and summarize some of the recent investigation into chemical exposures and metabolic disruption. Specifically, exposure to endocrine-disrupting chemicals (EDCs) during critical windows of susceptibility during development can lead to adverse metabolic outcomes. One EDC, nicotine, found in tobacco, can elicit metabolic disruption from direct or developmental exposure. Paternal tobacco smoking has been associated with metabolic outcomes in unexposed grandchildren. Paternal nicotine exposure can also elicit metabolic disruption in males of the next generation in rodents. Mechanisms underlying these alterations that arise upon paternal nicotine exposure are still being elucidated; however, one hypothesis is the alteration of sperm small non-coding RNAs leads to metabolic outcomes observed. Investigation into paternal nicotine exposure and a secondary challenge with a different metabolic disease risk factor in the next generation, such as diet, has not been studied. The next two data chapters detail findings of nicotine exposure at two different moments in life, adulthood and after paternal preconception exposure, and the metabolic outcomes that arise at the physiological and transcriptomic levels. In Chapter 2 of this dissertation, I demonstrate that direct exposure of the F0 generation to nicotine leads to physiological and transcriptomic metabolic outcomes. Chronic nicotine exposure elicited cardiometabolic disruption at the physiological and molecular levels. Nicotine exposure elicited altered plasma metabolites, blood glucose levels during metabolic testing in both male and female rodents. Specifically, nicotine exposure in males was associated with impaired insulin tolerance and decreased body weights. Hepatic transcriptomics reveal alterations in gene expression of biological processes involved with cardiovascular disease upon nicotine or tributyltin exposures. These alterations suggest that direct exposure to endocrine disrupting chemicals like nicotine or tributyltin elicits cardiometabolic alterations in mice. Furthermore, exposures to these endocrine disrupting chemicals may be associated with increased risk of cardiometabolic disease in humans. In Chapter 3 of this dissertation, I demonstrate that paternal exposure to nicotine predisposes offspring to metabolic disruption that is further exacerbated in the presence of a hypercaloric diet. I also show that there is a sexually dimorphic phenotype observed in the F1 generation upon paternal preconception nicotine exposure. Specifically, there are different metabolic processes altered in the sexes upon paternal nicotine exposure, such as modifications to hepatic gene expression in gluconeogenesis in F1 females and glycogenolysis in F1 males. F1 males also had decreases plasma glucagon, an important metabolite involved in glycogenolysis. Although physiological outcomes were mild, hepatic transcriptomics reveal alterations in gene expression of biological processes involved with lipid and xenobiotic metabolism suggesting alterations in the fat metabolism. Transcriptomic alterations to the metabolically relevant liver tissue ultimately reveal that there was metabolic disruption that arises from paternal nicotine exposure and is further exacerbated by a hypercaloric diet. Finally, in Chapter 4 of this dissertation, I summarize the findings from both data chapters and discuss how these findings shed light into the effects of direct and ancestral exposure to nicotine on adverse metabolic outcomes. The findings here further provide compelling evidence that paternal nicotine exposure can elicit long-lasting metabolic effects that can be further exacerbated by a hypercaloric diet that represents the diet 50% of the American population follows. This dissertation demonstrates that nicotine and hypercaloric diet, two types of environmental factors, can elicit cardiometabolic alterations at the physiological and molecular levels. Future studies will investigate potential mechanisms that link paternal nicotine exposure and metabolic outcomes observed.