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Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2015)

Epidemiologic studies suggest that pesticides are risk factors for Parkinson's Disease (PD) but predominantly assessed pesticide exposure as a broad category and often did not examine exposure modifying factors such as personal protective equipment (PPE) use and variants in genes that encode proteins involved in pesticide metabolism and distribution in the body. Only a handful have investigated household pesticide exposures alone. This dissertation research examined the relation between PD and exposures to pesticides from multiple exposure sources, including household use, occupational use, and ambient pesticide exposures from drift in addition to genetic variation in PON1 and ABCB1.

We recruited 360 incident PD cases and 827 population controls between 2001 through 2011 from central California, collected data on demographics, covariates, residential and occupational address history, and exposures to chemicals by telephone, and participants provided either whole blood or saliva samples.

Frequent use of any household pesticide increased PD risk by 47%; frequent use of products containing organophosphorus pesticides (OPs) increased risk more strongly by 71%, and frequent organothiophosphate use almost doubled the risk of PD. The largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs.

Ever occupational pesticide use for > 10 years doubled the risk of PD compared to never occupational pesticide users. PD risk was also increased with occupational use of fungicides, herbicides, insecticides, carbamates, OPs, and organochlorine (OC) pesticides. Surprisingly, we found higher risks among those who reported using PPE, possibly because these workers felt compelled to use PPE when handling toxic pesticides.

We replicated a prior finding of ABCB1 polymorphisms at both rs1045642 and rs2032582 modifying PD risk from occupational OC exposures. We also newly found that PD risk from occupational OP exposures is modified by these polymorphisms. However, we did not detect multiplicative interactions.

Our results suggest that exposures to OPs, carbamates, and OCs increase PD risk, and the risk from commonly used pesticides, specifically OCs and OPs, may be increased more strongly in individuals who are genetically susceptible to neurotoxic effects of pesticides.

    Cover page: An Investigation into Household and Occupational Pesticide Exposures with Genetic Variants as Risk Factors for Parkinson's Disease
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2017)

    Objective

    To study the influence of occupational pesticide use on Parkinson's disease (PD) in a population with information on various occupational, residential, and household sources of pesticide exposure.

    Methods

    In a population-based case control study in Central California, we used structured interviews to collect occupational history details including pesticide use in jobs, duration of use, product names, and personal protective equipment use from 360 PD cases and 827 controls. We linked reported products to California's pesticide product label database and identified pesticide active ingredients and occupational use by chemical class including fungicides, insecticides, and herbicides. Employing unconditional logistic regression, we estimated odds ratios and 95% confidence intervals for PD and occupational pesticide use.

    Results

    Ever occupational use of carbamates increased risk of PD by 455%, while organophosphorus (OP) and organochlorine (OC) pesticide use doubled risk. PD risk increased 110-211% with ever occupational use of fungicides, herbicides, and insecticides. Using any pesticide occupationally for >10years doubled the risk of PD compared with no occupational pesticide use. Surprisingly, we estimated higher risks among those reporting use of personal protective equipment (PPE).

    Conclusions

    Our findings provide additional evidence that occupational pesticide exposures increase PD risk. This was the case even after controlling for other sources of pesticide exposure. Specifically, risk increased with occupational use of carbamates, OPs, and OCs, as well as of fungicides, herbicides, or insecticides. Interestingly, some types of PPE use may not provide adequate protection during pesticide applications.
      Cover page: Occupational pesticide use and Parkinson's disease in the Parkinson Environment Gene (PEG) study
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2016)

      Objectives

      Little cigars and cigarillos are gaining in popularity as cigarette use wanes, mainly due to relaxed regulatory standards that make them cheaper, easier to buy individually, and available in a variety of flavors not allowed in cigarettes. To address whether they should be regulated as strictly as cigarettes, we investigated whether little cigar secondhand smoke (SHS) decreases vascular endothelial function like that of cigarettes.

      Methods

      We exposed rats to SHS from little cigars, cigarettes, or chamber air, for 10 minutes and measured the resulting acute impairment of arterial flow-mediated dilation (FMD).

      Results

      SHS from both little cigars and cigarettes impaired FMD. Impairment was greater after exposure to little cigar SHS than by cigarette SHS relative to pre-exposure values, although the post-exposure FMD values were not significantly different from each other.

      Conclusions

      Exposure to little cigar SHS leads to impairment of FMD that is at least equal to that resulting from similar levels of cigarette SHS. Our findings support the need to prevent even brief exposure to little cigar SHS, and support tobacco control policies that regulate little cigars as strictly as cigarettes.
        Cover page: Impairment of Endothelial Function by Little Cigar Secondhand Smoke
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2016)
        Psychological stress and glucocorticoids are associated with heightened cardiovascular disease risk. We investigated whether stress or cortisol would be associated with reduced circulating angiogenic cell (CAC) function, an index of impaired vascular repair. We hypothesized that minority-race individuals who experience threat in interracial interactions would exhibit reduced CAC function, and that this link might be explained by cortisol. To test this experimentally, we recruited 106 African American participants for a laboratory interracial interaction task, in which they received socially evaluative feedback from Caucasian confederates. On a separate day, a subset of 32 participants (mean age=26years, 47% female) enrolled in a separate biological substudy and provided blood samples for CAC isolation and salivary samples to quantify the morning peak in cortisol (the cortisol awakening response, CAR). CAC function was quantified using cell culture assays of migration to vascular endothelial growth factor (VEGF) and secretion of VEGF into the culture medium. Heightened threat in response to an interracial interaction and trait anxiety in vivo were both associated with poorer CAC migratory function in vitro. Further, threat and poorer sustained attention during the interracial interaction were associated with a higher CAR, which in turn, was related to lower CAC sensitivity to glucocorticoids. In vitro, higher doses of cortisol impaired CAC migratory function and VEGF protein secretion. The glucocorticoid receptor antagonist RU486 reversed this functional impairment. These data identify a novel, neuroendocrine pathway by which psychological stress may reduce CAC function, with potential implications for cardiovascular health.
          Cover page: Circulating angiogenic cell function is inhibited by cortisol in vitro and associated with psychological stress and cortisol in vivo
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2015)

          Background

          Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk.

          Objectives

          To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk.

          Methods

          In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD.

          Results

          For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions.

          Conclusions

          This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.
            Cover page: Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson’s disease
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2013)

            Background

            Household pesticide use is widespread in the USA. Since the 1970s, organophosphorus chemicals (OPs) have been common active ingredients in these products. Parkinson's disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. Here we investigate whether long-term use of household pesticides, especially those containing OPs, increases the odds of PD.

            Methods

            In a population-based case-control study, we assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Using logistic regression we estimated the effects of household pesticide use.

            Results

            Frequent use of any household pesticide increased the odds of PD by 47% [odds ratio (OR)=1.47, (95% confidence interval (CI): 1.13, 1.92)]; frequent use of products containing OPs increased the odds of PD more strongly by 71% [OR=1.71, (95% CI: 1.21, 2.41)] and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs.

            Conclusions

            We provide evidence that household use of OP pesticides is associated with an increased risk of developing PD.
              Cover page: Household organophosphorus pesticide use and Parkinson’s disease
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2016)

              Background

              Despite public awareness that tobacco secondhand smoke (SHS) is harmful, many people still assume that marijuana SHS is benign. Debates about whether smoke-free laws should include marijuana are becoming increasingly widespread as marijuana is legalized and the cannabis industry grows. Lack of evidence for marijuana SHS causing acute cardiovascular harm is frequently mistaken for evidence that it is harmless, despite chemical and physical similarity between marijuana and tobacco smoke. We investigated whether brief exposure to marijuana SHS causes acute vascular endothelial dysfunction.

              Methods and results

              We measured endothelial function as femoral artery flow-mediated dilation (FMD) in rats before and after exposure to marijuana SHS at levels similar to real-world tobacco SHS conditions. One minute of exposure to marijuana SHS impaired FMD to a comparable extent as impairment from equal concentrations of tobacco SHS, but recovery was considerably slower for marijuana. Exposure to marijuana SHS directly caused cannabinoid-independent vasodilation that subsided within 25 minutes, whereas FMD remained impaired for at least 90 minutes. Impairment occurred even when marijuana lacked cannabinoids and rolling paper was omitted. Endothelium-independent vasodilation by nitroglycerin administration was not impaired. FMD was not impaired by exposure to chamber air.

              Conclusions

              One minute of exposure to marijuana SHS substantially impairs endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco SHS. Impairment of FMD does not require cannabinoids, nicotine, or rolling paper smoke. Our findings in rats suggest that SHS can exert similar adverse cardiovascular effects regardless of whether it is from tobacco or marijuana.
                Cover page: One Minute of Marijuana Secondhand Smoke Exposure Substantially Impairs Vascular Endothelial Function
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2023)
                AIMS: Acute myocardial infarction (MI) causes inflammation, collagen deposition, and reparative fibrosis in response to myocyte death and, subsequently, a pathological myocardial remodelling process characterized by excessive interstitial fibrosis, driving heart failure (HF). Nonetheless, how or when to limit excessive fibrosis for therapeutic purposes remains uncertain. Galectin-3, a major mediator of organ fibrosis, promotes cardiac fibrosis and remodelling. We performed a preclinical assessment of a protein inhibitor of galectin-3 (its C-terminal domain, Gal-3C) to limit excessive fibrosis resulting from MI and prevent ventricular enlargement and HF. METHODS AND RESULTS: Gal-3C was produced by enzymatic cleavage of full-length galectin-3 or by direct expression of the truncated form in Escherichia coli. Gal-3C was intravenously administered for 7 days in acute MI models of young and aged rats, starting either pre-MI or 4 days post-MI. Echocardiography, haemodynamics, histology, and molecular and cellular analyses were performed to assess post-MI cardiac functionality and pathological fibrotic progression. Gal-3C profoundly benefitted left ventricular ejection fraction, end-systolic and end-diastolic volumes, haemodynamic parameters, infarct scar size, and interstitial fibrosis, with better therapeutic efficacy than losartan and spironolactone monotherapies over the 56-day study. Gal-3C therapy in post-MI aged rats substantially improved pump function and attenuated ventricular dilation, preventing progressive HF. Gal-3C in vitro treatment of M2-polarized macrophage-like cells reduced their M2-phenotypic expression of arginase-1 and interleukin-10. Gal-3C inhibited M2 polarization of cardiac macrophages during reparative response post-MI. Gal-3C impeded progressive fibrosis post-MI by down-regulating galectin-3-mediated profibrotic signalling cascades including a reduction in endogenous arginase-1 and inducible nitric oxide synthase (iNOS). CONCLUSION: Gal-3C treatment improved long-term cardiac function post-MI by reduction in the wound-healing response, and inhibition of inflammatory fibrogenic signalling to avert an augmentation of fibrosis in the periinfarct region. Thus, Gal-3C treatment prevented the infarcted heart from extensive fibrosis that accelerates the development of HF, providing a potential targeted therapy.
                  Cover page: Inhibition of galectin-3 post-infarction impedes progressive fibrosis by regulating inflammatory profibrotic cascades.
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