Benzoates - an Obesogenic Endocrine Disrupting Chemical

Study Overview
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Brief Summary
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The benzoic acid derivatives sodium and potassium benzoate are preservatives that are commonly added to food and beverages to inhibit microbial growth and prevent spoilage. In the US the major source of benzoate intake is beverages. Studies have shown that piglets or chicks fed low levels of benzoic acid have greater feed efficiency and gain more weight than control fed animals. It has also been shown that benzoic acid inhibits the release of a key metabolic hormone, leptin, from isolated adipocytes (fat cells). Inadequate leptin levels result in increased appetite, decreased metabolic rate, weight gain, insulin resistance and increased diabetes risk. The primary aim of the proposed research is to directly determine if benzoate consumption in human volunteers results in lower levels of leptin, decreased metabolic rate and increased insulin resistance. If so this would implicate benzoic acid as an obesogen and would help inform more effective approaches to obesity prevention and treatment. A secondary aim of the study is to establish a connection between benzoate exposure and biomarkers in urine that can be used to help treat obese patients.

Detailed Description
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Our hypothesis is that benzoic acid is an obesogenic xenobiotic that attenuates the leptin signaling pathway resulting in lower metabolic rate and hence a propensity to weight loss non-responsiveness. This hypothesis will be addressed in this pilot project via the following Specific Aims: Aim 1. Determine if dietary benzoate attenuates leptin levels and metabolic rate in human subjects. Twenty heathy adolescents and young adults (age 18-25 yrs.) who are either overweight (BMI 25-29.9) or obese (BMI ≥ 30) will be studied. Following a 14 day period of avoiding benzoate containing beverages (washout period) subjects will then consume 36 oz./day of benzoate containing beverages (  3.9 - 4.5 mg benzoate/kg body weight per day exposure) for 7 days (exposure period). Fasting plasma samples will be collected pre and post-exposure and leptin, adiponectin, insulin and glucose levels will be compared. Indirect calorimetry will be used to compare resting energy expenditure pre-and post-exposure. Aim 2. Validate the use of urinary hippurate and glycine to assess benzoate exposure. An early morning void urine samples will be collected pre-and post-exposure. Non-targeted NMR-based metabolomics analysis will be used to compare changes in individual subject's urinary metabolome using pre- and post-exposure as the phenotypic anchors.

Official Title
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Benzoic Acid in Beverages: Establishing a Link Between Urinary Metabolites, Metabolic Dysregulation and Weight Loss Failure

Conditions
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Obesity, Metabolic Syndrome

Intervention / Treatment
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* Other: Benzoic acid washout and exposure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Young adult (18-30 yrs) Healthy non-smoker Either overweight (BMI >25 but <30) or obese (BMI >30) Has or can obtain transportation to study site Able to provide written consent in English Exclusion Criteria: Metabolic disease Diabetes mellitus Hypothyroidism Use of medication that may influence metabolism Anti-hyperglycemic agents Thyroid hormone Stimulants for ADD/ADHD Atypical anti-psychotics Weight loss medications Benzoate sensitivity Known pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Pre/post exposure comparison
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benzoic acid washout and exposure<br>All subjects will be in this arm which employs a pre-post exposure design. Subjects will undergo a 2 week washout period where they avoid consumption of benzoate containing beverages. Then there is a 1 week exposure period comprising daily consumption of benzoate containing beverages to result in up to 5 mg/kg per day benzoic acid intake. | Other: Benzoic acid washout and exposure<br>* see above<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic rate | Metabolic rate as measured by indirect calorimetry | measured following 1 week dietary exposure to benzoic acid. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leptin levels | Circulating levels of the adipokine leptin will be measured using ELISA | measured following 1 week dietary exposure to benzoic acid | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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benzoic acid, endocrine disrupting chemicals, leptin, metabolic rate