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Phthalates

New Articles on Diabetes and Chemicals

Phthalates are widely used chemicals that soften PVC plastic, and are also used in cosmetics, perfumes, and industrial paints and solvents. DEHP is the most commonly used phthalate, used to manufacture a variety of products, including food packaging and medical devices. It can enter people's bodies by leaching out of these products (Feige et al. 2007). Phthalate metabolites are breakdown products of phthalates found in people's bodies. Women tend to be exposed to higher levels of phthalates than men, due to their higher use of personal care products. In addition, Blacks, Mexican Americans, and women living in poverty are exposed to the highest levels of these compounds (James-Todd et al. 2012). Phthalates are endocrine (hormone) disruptors.  

Type 2 diabetes, insulin resistance, and body weight

Longitudinal studies in humans

The strongest evidence for the ability for environmental exposures to contribute to the development of diabetes comes from longitudinal studies. These are studies that take place over a period of time, where the exposure is measured before the disease develops.

The first longitudinal study of phthalates and type 2 diabetes has just been published using data from the U.S. Nurses Health Studies 1 and 2. In the Nurses Health Study 1, which includes older women (average age 66), total phthalate levels were not associated with type 2 diabetes. However, in the Nurses Health Study 2, which includes middle-aged women (average age 46), total phthalate levels were associated with type 2 diabetes. Thus, phthalate exposures may be associated with the risk of type 2 diabetes among middle-aged women, but not older women. These findings may be due to menopausal status (although chance cannot be ruled out). While the younger women had higher levels of phthalates than the older women, these differences did not explain the findings. Note that this paper also found similar results for BPA exposure levels (Sun et al. 2014).

A similar study by many of the same authors, also based on the Nurses Health Studies, found that women (without diabetes) with the highest levels of some phthalate (and BPA) exposures gained more weight during the 10 year follow-up period than those with lower levels of exposures (Song et al. 2014). For an article describing this study, see Household chemicals linked to slight weight gain, published by Environmental Health News.

A study of elderly Korean adults found that urinary phthalate metabolite levels (from DEHP) were associated with increased insulin resistance, especially among women and those with diabetes. A marker of oxidative stress was also higher in those with higher insulin resistance and phthalate levels (Kim et al. 2013). In elderly Swedish women (not men), the phthalate MiBP was related to increased abdominal body fat two years later (Lind et al. 2012). 

In New York City children, certain phthalate exposures measured at age 6-8 were associated with a higher body mass index and waist circumference one year later (Teitelbaum et al. 2012). 

Exposure during development

Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life. Prenatal exposure to phthalates was associated with changes in BMI and head circumference during the first year of life (de Cock et al. 2014).

Cross-sectional studies in humans

Cross-sectional studies are studies that measure exposure and disease at one point in time. These provide weaker evidence than longitudinal studies, since the disease may potentially affect the exposure, and not vice versa.

A study of U.S. adult women found that levels of several phthalates were associated with a higher risk of diabetes. Women with the highest levels of some phthalates had twice the risk of diabetes as those with the lowest levels (James-Todd et al. 2012). For an article about this study, see Plastics chemicals linked to diabetes in women; blacks and Hispanics most exposed, published by Environmental Health News. In an expansion of this study, some of the same researchers found that phthalate levels were associated with higher fasting blood glucose levels, fasting insulin levels, and increased insulin resistance. These associations were strongest in Mexican Americans and non-Hispanic blacks, suggesting that these groups may be more vulnerable to phthalate exposures relating to diabetes (Huang et al. 2014).

A different study found that phthalate levels were associated with increased insulin resistance in U.S. adolescents (Trasande et al. 2013a).

In a study of Swedish elderly people, researchers found that 3 of 4 types of phthalate metabolites were associated with type 2 diabetes prevalence. The phthalate metabolites linked to diabetes included MMP, MiBP, and MEP, which are breakdown products of phthalates found in body care products. MiBP was related to poor insulin secretion, while MMP and MEP were related to insulin resistance. The phthalate metabolite MEHP, which is a breakdown product of the plasticizer DEHP, was not associated with diabetes in this study (Lind et al. 2012). Phthalates activate certain hormone receptors called PPARs. PPARs are known to influence blood glucose levels, via insulin resistance, insulin secretion, and fat formation.  Interestingly, pharmaceutical drugs that have the opposite effect on PPARs are used to treat type 2 diabetes, by decreasing insulin resistance (Lind et al. 2012).

Phthalates have also been associated with diabetes in a study of Mexican women. That study found that levels of three types of DEHP metabolites were higher in adult women with diabetes than those without diabetes. The results suggest that phthalate exposures may play a role in diabetes development (Svensson et al. 2011). In elderly Swedes, various phthalates were associated with fasting blood glucose levels, as well as cholesterol and blood pressure (Olsen et al. 2012).

In a U.S. study, levels of several phthalate metabolites were associated with increased insulin resistance and abdominal obesity in U.S. men (Stahlhut et al. 2007). In another U.S. study of people aged 6-80, various phthalate metabolites were associated with higher body mass index (BMI) and waist circumference in men aged 20-59. Effects in women were not as consistent. In some ages, exposures was associated with lower BMI (Hatch et al. 2008; Hatch et al. 2010). In a third U.S. study, a number of phthalates were associated with obesity in men and women, with differences depending on the type of phthalate, age, and sex (Buser et al. 2014). In a fourth U.S. study, certain phthalate metabolites were associated with an increased risk of overweight/obesity and BMI in black children, but not children of other ethnic groups (Trasande et al. 2013b). 

In Chinese schoolchildren, levels of certain phthalates were associated with increased BMI or waist circumference (Wang et al. 2013). And in Korean children, certain phthalates were associated with obesity (Choi et al. 2014). Another Chinese study found that levels of certain phthalates were associated with higher BMI and fat distribution in boys over 10, but lower fat distribution in girls under 10 (Zhang et al. 2014).

Laboratory studies

In animals, rats given the phthalate DEHP developed symptoms of diabetes, including higher blood sugar and lower insulin levels. The changes reversed when the exposure was removed (Gayathri et al. 2004).  A study at the cellular shows the direct adverse effect of DEHP on the gene expression relating to insulin and glucose, suggesting that DEHP exposure may have a negative influence on insulin signaling (how the body responds to insulin) (Rajesh and Balasubramanian, 2013). Short term treatment of rats with a number of different phthalates found that some of the phthalates (DEHP, MEHP, and MBeP) caused high blood glucose levels (Kwack et al. 2010). Rats treated with DEP had higher blood glucose levels than controls as well (Pereria and Rao, 2006).

Adult rats given DEHP for a month developed high blood sugar, insulin resistance, and other changes associated with diabetes. Those given DEHP plus the antioxidant vitamins E and C, however, did not develop these symptoms of diabetes (Rajesh et al. 2013; Srinivasan et al. 2011). These vitamins essentially prevented diabetes in phthalate-exposed mice-- a sign of how nutrition and chemical exposures may interact to affect disease risk.
 
In laboratory studies, the phthalate MEHP was found to promote the formation of fat cells (DEHP is converted to the metabolite MEHP when ingested) (Feige et al. 2007). The phthalate DCHP has also been shown to promote the formation of fat cells (Sargis et al. 2009). DCHP promotes fat formation through mechanisms involving the hormone glucocorticoid (Sargis et al. 2010). Disturbed glucocorticoid action is associated with a number of conditions, including type 2 diabetes, obesity, and autoimmune disease (Odermatt et al. 2006).

Desvergne et al. (2009) discuss potential mechanisms of phthalate action on obesity, via what they call "metabolic disruptors." MEHP promotes fat formation through metabolic disruption and by affecting gene expression (Feige et al. 2007Ellero-Simatos et al. 2011). 

Exposure during development

When pregnant and lactating rats were given DEHP, their offspring developed abnormal beta cells, and alternations of the genes controlling beta cell function at the time of weaning. In adulthood, the female offspring had high blood glucose, impaired glucose tolerance and impaired insulin secretion. The adult males had increased insulin secretion. These results suggest that developmental exposure to phthalates can lead to beta cell dysfunction and glucose abnormalities, and is a potential risk factor for diabetes development (Lin et al. 2011).

Female mice that were exposed to phthalates had higher body weight, more fatty tissue, and higher food intake than unexposed mice. Their offspring, only exposed during fetal development and while nursing, also exhibited similar metabolic changes, including higher body weight and more fatty tissue (Schmidt et al. 2012). For an article describing this study, see Long-term outcomes after phthalate exposure: food intake, weight gain, fat storage, and fertility in mice, published in Environmental Heath Perspectives.

Mice exposed to the phthalate MEHP in the womb had higher blood glucose levels, gained more weight, and had higher cholesterol levels later in life than unexposed mice (Hao et al. 2012). A similar study by the same authors found that another phthalate, DEHP, had the same effects (Hao et al. 2013). A study of male rats exposed to DEHP in the womb found that the chemical exposure led to fatty tissue inflammation as well as an increased immune response. DEHP may affect the development of pre-fat cells into fat cells, without affecting overall body weight (Campioli et al. 2014). Rats exposed in the womb to the phthalate DiBP had lower leptin and insulin levels later in life than controls, suggesting metabolic dysfunction (Boberg et al. 2008).

Rats exposed to low levels of DEHP only from nursing from their exposed mothers were found to have higher blood sugar and changes in insulin signaling later in life (Mangala Priya et al. 2014). Similarly, rats exposure to DEHP only in the womb were found to have higher blood sugar and insulin levels, and changes in insulin signalling later in life (Rajesh and Balasubramanian, 2014).

Laboratory studies have established that epigenetic modifications caused by developmental exposure to environmental chemicals can induce alterations in gene expression that may persist throughout life. In the case of phthalates, some of these effects can be transferred from one generation to following generations (Singh and Li, 2012).

Chemicals in combination

What are the effects of mixtures of chemicals? Very few studies have been done on chemicals in combination with one another, although that is how humans are exposed. One study exposed mice -- starting from before conception -- throughout life to very low doses (at levels thought to be "safe") of a combination of chemicals commonly found in food, including phthalates, BPA, dioxin, and PCBs, and fed them a high-fat diet. As adults, compared to unexposed controls, pollutant-exposed females developed impaired glucose tolerance, and males showed liver and cholesterol effects, as well as epigenetic changes (Naville et al. 2013).

Transgenerational effects

Another study of developmental exposure to mixtures of chemicals is even more alarming. It tested a mixture of BPA and two types of phthalates (DEHP and DBP), both found in plastics. Pregnant rats were exposed to this mixture, and outcomes evaluated in their offspring, for 3 generations. The third generation offspring (the exposed mothers' great-grandchildren), had higher rates of obesity (in addition to many other health issues). The mechanism involved not changes to DNA, but epigenetic changes that were passed down from one generation to the next (Manikkam et al. 2013). You can listen to a recording of a call with one of the authors of this study, Transgenerational Effects of Prenatal Exposure to Environmental Obesogens in Rodents, sponsored by the Collaborative on Health and the Environment.

Type 1 diabetes and autoimmunity

There are no studies of type 1 diabetes in relation to phthalate exposure.

In a series of three studies, researchers examined the effects of phthalates on autoimmunity in mice. They found that after exposure to phthalates, different types of mice developed autoantibodies. But, only the autoimmune-prone mice went on to develop disease. They conclude that phthalates seem to be harmful only to susceptible strains of mice, while other strains are protected (Lim and Ghosh 2003; Lim and Ghosh 2004; Lim and Ghosh 2005). A study mentioned above found that male rats exposed to DEHP in the womb had an increased immune response, as well as chronic, low-grade systemic inflammation (Campioli et al. 2014).

Gestational diabetes

A study of pregnant women across Canada, did not find a statistically significant association between women's levels of phthalates and gestational diabetes. However, the did find a suggestion that levels of 6 phthalates were slightly lower in the women who developed gestational diabetes than in women who did not (Shapiro et al. 2013).

Diabetes complications

Phthalate levels have been associated with the risk of heart disease (Wiberg et al. 2014), although studies of people with diabetes remain to be conducted.

The bottom line

Various types of phthalates are associated with diabetes, excess weight, and insulin resistance in human studies, thus far mostly cross-sectional. These conclusions are supported by animal studies. There is some evidence that exposure to phthalates, and levels in the general population, may contribute to the development of type 2 diabetes. While this "metabolic disruption" is likely more significant for type 2 diabetes than type 1, the ability of phthalates to also promote the development of autoimmunity in animals is cause for concern.

A review of phthalates in obesity concludes, "Many in vitro studies indicate that phthalates are likely obesogens, promoting obesity via several mechanisms, including activation of PPARs, antithyroid effects, and epigenetic modulation. The fetal period appears to be a critical window for exposure, and differential effects are observed depending on the dose of phthalates received and gender. Recent human studies have examined the possible effects of phthalate exposure on the development of obesity, although most of them are cross-sectional and short-term prospective studies. Although the random concentrations of phthalate metabolites have good reproducibility, large-scaled longitudinal study including measures at different life ages is needed to establish the impact of phthalate exposure on the obesity epidemic" (Kim and Park, 2014).

References

To download or see a list of all the references cited on this page, see the collection Phthalates and diabetes/obesity in PubMed.

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