Evolving Connections Between Phthalates and Obesity/Type 2 Diabetes

In short: scientific evidence increasingly finds that phthalates are connected with Obesity and Type 2 Diabetes. More research is needed.

The following excerpts come from  peer-reviewed studies published in 2014 and 2015. Note, the term “epigenetics” refers to a process in which the activity of a gene can be controlled, blocked or overexpressed by mechanisms that do not change the underlying DNA code. An epigenetic modification can have the same sort of effect as a mutation.

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Image from: “New risk factors for obesity and diabetes: Environmental chemicals”

New risk factors for obesity and diabetes: Environmental chemicals (Full Article Available For Free)

The global prevalence of diabetes and associated metabolic diseases has increased dramatically in recent decades.

The International Diabetes Federation estimates that 382 million people worldwide have diabetes (8.3% of adults), and that 592 million people (10% of adults) will have diabetes in 2035[1].

The estimated population with diabetes is greater in the Western Pacific than other regions. In Korea, the prevalence of diabetes is 12.4%, or an estimated 4.01 million people[2]. Type 2 diabetes accounts for more than 95% of the diabetes cases in Korea.

Patients with diabetes and society pay tremendous medical costs for diabetes treatment and managing its complications.

In 2013, global health spending on diabetes reached at least US$548 billion, and this is estimated to exceed US$627 billion by 2035[1].

Efforts to reduce the burden of diabetes involve clarification of its pathogenesis and the risk factors for diabetes.

The main pathogenesis of type 2 diabetes involves β-cell dysfunction in the pancreas and peripheral insulin resistance. Factors contributing to the development of type 2 diabetes include old age, obesity, lack of physical activity, a family history of diabetes and a genetic predisposition.

However, these traditional risk factors alone cannot explain the rapidly increasing prevalence of diabetes worldwide (Figure 1).

Obesity and diabetes: from genetics to epigenetics

In spite of the intense efforts to identify genetic predisposing variants, progress has been slow and success limited, and the common obesity susceptibility variants identified only explains a small part of the individual variation in risk.

Moreover, there is evidence that the current epidemic of obesity and diabetes is environment-driven. Recent studies indicate that normal metabolic regulation during adulthood besides requiring a good balance between energy intake and energy expenditure, can be also affected by pre- and post-natal environments.

In fact, maternal nutritional constraint during pregnancy can alter the metabolic phenotype of the offspring by means of epigenetic regulation of specific genes, and this can be passed to the next generations.

Studies focused on epigenetic marks in obesity found altered methylation and/or histone acetylation levels in genes involved in specific but also in more general metabolic processes.

Recent researches point out the continuous increase of “obesogens”, in the environment and food chains, above all endocrine disruptors, chemicals that interfere with many homeostatic mechanisms.

Taken into account the already existing data on the effects of obesogens, and the multiple potential targets with which they might interfere daily, it seems likely that the exposure to obesogens can have an important role in the obesity and diabesity pandemic.

Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts

Extensive research has established the role of lifestyle, diet, and genetic variations in the etiology of type 2 diabetes (T2D) (Qi et al. 2008). Meanwhile, emerging evidence has led to a novel hypothesis that some of these chemicals, such as bisphenol A (BPA) and phthalates, may also be related to the rising epidemics of obesity and T2D (Casals-Casas and Desvergne 2011). Both classes of chemicals are produced in large quantities worldwide and have wide industrial applications (Casals-Casas and Desvergne 2011; Hauser and Calafat 2005) and can be detected ubiquitously in human urines (Calafat et al. 2008; Silva et al. 2004).

Animal experiments suggest that, in addition to its well-known estrogenic effects, BPA may also interfere with multiple pathways related to T2D, including impaired beta-cell function (Alonso-Magdalena et al. 2006), liver dysfunction (Bindhumol et al. 2003; Nakagawa and Tayama 2000), dysregulation of glucose metabolism and adiponectin release in adipocytes (Ben-Jonathan et al. 2009; Hugo et al. 2008), and disruption of thyroid hormone functions (Moriyama et al. 2002). Experimental evidence suggests that phthalates may also affect the liver and interfere with adipocyte biology and glucose metabolism through effects on peroxisome proliferator-activated receptors (PPARs) (Desvergne et al. 2009). Despite the accumulation of evidence from animal studies, evidence among humans for associations of BPA and phthalates with T2D has been limited to cross-sectional studies, with mixed findings (James-Todd et al. 2012; LaKind et al. 2012; Lang et al. 2008; Lind et al. 2012b; Ning et al. 2011; Shankar and Teppala 2011; Silver et al. 2011; Svensson et al. 2011).

Conclusions: These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives.

Urinary phthalate metabolites are associated with insulin resistance in obese subjects

Phthalates are potentially involved in the development of type 2 diabetes mellitus. In a cohort of 123 obese subjects, 10 phthalate metabolites were analyzed. An oral glucose tolerance test was performed and various estimates of insulin resistance and beta-cell function were calculated. After adjustment for age, physical activity level, smoking behavior, medication use and body mass index, several phthalate metabolites were linked to markers of glucose tolerance and insulin resistance.

 What Are We Putting in Our Food That Is Making Us Fat? Food Additives, Contaminants, and Other Putative Contributors to Obesity

Abstract: The “chemical obesogen” hypothesis conjectures that synthetic, environmental contaminants are contributing to the global epidemic of obesity. In fact, intentional food additives (e.g., artificial sweeteners and colors, emulsifiers) and unintentional compounds (e.g., bisphenol A, pesticides) are largely unstudied in regard to their effects on overall metabolic homeostasis.

With that said, many of these contaminants have been found to dysregulate endocrine function, insulin signaling, and/or adipocyte function. Although momentum for the chemical obesogen hypothesis is growing, supportive, evidence-based research is lacking.

In order to identify noxious synthetic compounds in the environment out of the thousands of chemicals that are currently in use, tools and models from toxicology should be adopted (e.g., functional high throughput screening methods, zebrafish-based assays).

Finally, mechanistic insight into obesogen-induced effects will be helpful in elucidating their role in the obesity epidemic as well as preventing and reversing their effects.

In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring (Open access)

Background: Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to increase the flexibility of polyvinyl chloride. DEHP and its active metabolite mono-(2-ethylhexyl) phthalate are detected in many biological fluids during fetal and postnatal life.

In rodent models, in utero DEHP exposure has been shown to alter sexual organ development, decrease testosterone and aldosterone production, increase body and epididymal adipose tissue weight, and raise serum lipids and glucose levels in male offspring.

Objectives: The objective of this study is to characterize the effects of in utero DEHP exposure on adipose tissue development and function in male offspring.

Results: Global gene expression analyses of postnatal day 60 male offspring that were exposed in utero to 300 mg DEHP per kg per day revealed increased expression of immune response and inflammation markers, and increased expression of differentiation pathway genes in the epididymal whole-adipose tissue and isolated stromal vascular fraction. C-reactive protein and tumor necrosis factor (TNF) serum levels were increased in the 300 mg DEHP in utero-exposed offspring. TNF levels in adipose tissue homogenates were increased in the 50 and 300 mg DEHP in utero-exposed offspring. Immunofluorescence studies revealed focal macrophage infiltration in whole-adipose tissue confirmed by increased CD163 tissue content.

Conclusions:In utero DEHP exposure promotes local adipose tissue inflammation and chronic low-grade systemic inflammation. Moreover, evidence is presented, suggesting that DEHP increases the differentiation capacity of the pre-adipocytes of male offspring without affecting total body weight.


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