Phtalates can be found in a variety of products such as cosmetics, shampoos, soaps, lubricants, pesticides and paints. Food is the main tool responsible for the human exposure to phthalates that are often contained in wrapping materials or during the food processing (Wams 1987). The metabolic transformation of phtalates after the exposure starts with hydrolytic breakup of diesters (Meeker et al. 2012). The hydrolytic monoesters that result from this molecular step are then excreted in the urine or are further processed as glucuronide conjugates, some of which are oxidized. The main metabolites of phtalates are: di-2-ethylhexyl phthalate (DEHP), mono-ethylphthalate (MEP), mono-butyl phthalate (MBP), mono-benzylphthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-(3-carboxypropyl) phthalate(MCPP) (Frederiksen et al. 2007). The free monoesters, glucuronide conjugates and the oxidative metabolites are used as urinary markers of phtalate exposure (Kato et al. 2004). A growing body of studies focused on the phtalate-related diseases. A link has been found between phtalate exposure and cancer (Erkekoglu and Kocer-Gumusel 2014), developmental outcomes (Bay et al. 2006), thyroid function (Andra and Makris 2012) and fertility (Meeker 2010). Recent evidences pointed out phtalates as cardiovascular health disruptors. This hypothesis was based on studies that reported an association of phtalate exposure with cardiovascular risk factors such as obesity, lipid metabolism, blood pressure and atherosclerosis.

The correlation between phtalates and obesity has been assessed in several studies. Most of the results come from the NHANES studies and surveys carried out in the USA in order to obtain a random sample of the civilian non-institutionalized population for a given survey cycle. Stalhult et al. (2007) by measuring waist circumference (WC) in adult the US male enrolled in the National Health and Nutrition Examination Survey (NHANES) 1999–2002 investigated whether the phthalate metabolites MBP, MBzP, MEHP, MEP, MEHHP and MEOHP were predictor of abdominal obesity. MBzP, MEHHP, MEOHP and MEP have been identified as predictor of abdominal obesity, thus suggesting that the exposure to these phtalate metabolites may contribute to the burden of obesity (Stahlhut et al. 2007). This study included only male subjects while Hatch et al. subsequently analyzed the same NHANES database but including both genders (Hatch et al. 2008). The endpoints of interest in Hatch’s study were BMI and WC.

The main findings were the association of MBzP, MEOHP, MEHHP, MEP and MBP with BMI and WC in males aged 20–59 and the association of MEP to BMI and WC in adolescent girls (Hatch et al. 2008). Trasande et al. (2013a, b) focused their study on the 2003–2008 National Health and Nutrition Examination Survey performing a cross-sectional analysis of 2884 children (aged 6–19 years). The endpoints of interest were 2000 CDC reference-based BMI z-scores and binary variables of overweight and obesity that were defined using BMI z-score cutoffs of 85th and 95th percentile, respectively. The interesting finding of this study was that the association between anthropometric measures with phtalate metabolites was found to be race/ethnicity specific. In fact each log unit increase in low molecular weight metabolites was associated with 21 and 22 % increases in odds (95 % CI 1.05–1.39 and 1.07–1.39, respectively) of overweight and obesity and a 0.090-SD unit increase in BMI z-score (95 % CI 0.003–0.18), among non-Hispanic blacks but not in other racial/ethnic subgroup (Trasande et al. 2013a, b). Using data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, Lind et al. assessed whether circulating concentrations of phthalates were related to different indices of obesity (Lind et al. 2012a). Serum phtalate metabolites levels were assessed at baseline and dual-energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging (MRI) assessments were performed 2 years later. The results of Lind et al. were presented separately by gender. In women, MiBP levels were positively correlated with WC, total fat mass and trunk fat mass assessed by DXA, as well as to subcutaneous adipose tissue assessed by MRI while mono-methyl phthalate (MMP) concentrations were related to trunk fat mass and the trunk/leg-ratio assessed by DXA, although this association was less powerful than the association with MiBP. No association between phtalate metabolites and anthropometric indices was found in men. The interesting study performed by Lind et al. has the limit that could not be considered as a truly longitudinal study and this is because exposure assessment was performed 2 years before the outcome ascertainment; thus, the follow-up status of participants could not be corresponding to the status at baseline (Lind et al. 2012a) (Fig. 1).

Fig. 1
figure 1

Summary of phtalate metabolites associated with obesity, type 2 diabetes, atherosclerosis and hypertension. Abbr. di-2-ethylhexyl phthalate (DEHP), mono-ethylphthalate (MEP), mono-butyl phthalate (MBP), mono-benzylphthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-(3-carboxypropyl) phthalate(MCPP), mono-n-butyl phthalate (MnBP), mono-methyl phthalate (MMP), di-(2- ethylhexyl) phthalate metabolites (ΣDEHP)

The association of phtalates and phtalate metabolites as indices of obesity could be explained by a molecular viewpoint. In fact, MEHP directly binds and activates PPARγ, thus promoting adipogenesis. Importantly, MEHP induces a selective activation of different PPARγ co-regulators including Med1 and PGC-1α, but not p300 and SRC (Feige et al. 2007). In addition to PPARγ, phthalate monoesters have been reported to activate PPARα and PPARβ both in mice and humans with similar sensitivity (Bility et al. 2004). Hurst et al. investigated the activation of PPARα and PPARγ by phthalate monoesters using cell-based trans-activation assays and by monitoring PPAR target gene expression (PPARα) or PPAR-dependent adipocyte differentiation (PPARγ) (Hurst and Waxman 2003). Among the phtalate monoesters, MBzP and MEHP have been shown to activate both human and mouse PPARα and PPARγ while mono-methyl, mono-n-butyl, dimethyl or diethyl esters of phthalic acid did not (Hurst and Waxman 2003). Although the exposure of 3T3-L1 cell model to MEHP induced expression of PPARγ as well as its target genes, Hao et al. aimed to demonstrate whether this results were confirmed in vivo and in particular whether perinatal exposure to MEHP may have any effect on filial adipogenesis (Hao et al. 2012). At postnatal day 60, an increased in adipose tissue deposition was observed in male offspring of mother exposed to MEHP during pregnancy, thus showing that in vivo results were consistent with in vitro results (Hao et al. 2012).

Phtalates and their metabolites also seem to be involved in glucose derangements. A cross-sectional study performed by Svensson et al. (2011) assessed the association between phtalate and self-reported diabetes in 221 healthy Mexican women that were previously enrolled as controls in an on-going case–control study for breast cancer. Higher concentrations of DEHP metabolites such as MEHHP, MEOHP and MECPP but lower levels of MBzP have been found in patients with diabetes compared to participants without diabetes (Svensson et al. 2011). These results also were confirmed by James–Todd et al. (2012) in a cross-sectional study on a large population 2350 women between 20 and 79 years of age who participated in the NHANES (2001–2008). In this study, the endpoint of interest also was self-reported diabetes. After dividing the population in quartiles, women with higher levels of mono-n-butyl phthalate (MnBP),MiBP, MBzP, MCPP and three di-(2- ethylhexyl) phthalate metabolites (ΣDEHP) had an increased odds of diabetes compared with women with the lowest levels of these phthalates. Women in the highest quartile for MBzP and MiBP had almost twice the odds of diabetes compared with women in the lowest quartile (James-Todd et al. 2012). Lind et al. (2012b) reported an increased prevalence of diabetes with increasing urinary excretion of MMP, MiBP and MEP in 1016 subjects, aged 70 years, belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. In particular, MiBP was mainly related to decreased insulin secretion assessed by fasting proinsulin-to-insulin ratio, whereas MEP and MMP mainly were related to insulin resistance assessed by HOMA index (Lind et al. 2012b). In the same cohort of study, Olsén et al. (Olsén et al. 2012) found a significant association between MiBP and fasting glucose. There are few studies that provide an explanation of the link between glucose derangements and exposure to phtalates and their metabolites from a molecular viewpoint. As well known, an imbalance between the oxidative stress production and antioxidant defenses may play an important role in inducing alterations in insulin signaling pathways (Lamb and Goldstein 2008). Marker of oxidative stress such as malondialdehyde has been reported to be increased by exposure to phthalates and to correlate in a dose–response manner with ∑DEHP and insulin resistance index (Kim et al. 2013). The hypothesis that could explain this link is that exposure to phthalates induces mitochondrial dysfunction and thus oxidative stress leading to the onset of insulin resistance. Latter, phtalates have been reported to decrease serum insulin levels in rats administered with DEHP at a low level of 750 microg/100 g body weight on alternate days for 14 days (Gayathri et al. 2004) and to interfere with insulin signaling in adipose tissue of Wistar rats (Rajesh et al. 2013). All these pathological mechanisms could lead to rises in blood glucose (Fig. 1).

Phtalates and their metabolites have been reported to be associated with blood pressure and hypertension. An accurate assessment of PIVUS study revealed a significant inverse correlation between MEP and both systolic (SBP) and diastolic blood pressure (DBP) (Olsén et al. 2012). Phtalate metabolites such as MBP, MEHHP, MEOHP, MEHP and ΣDEHP were associated with SBP, but none of these metabolites was related to DBP in the Trasande et al. study (Trasande et al. 2013b).

A tight relation between DEHP and blood pressure was found in a subsample of US children aged 6–19 years enrolled in the National Health and Nutrition Examination Survey between 2003 and 2008. For each log unit increase in DEHP metabolites, a 0.041 SD unit increase in systolic BP z-score was identified (Trasande et al. 2013b). MBzP concentrations have been associated with increased DBP and risk of pregnancy-induced hypertensive diseases in 369 women of the Health Outcomes and Measures of the Environment Study, a prospective birth cohort of low-risk pregnant women recruited between March 2003 and January 2006 (Werner et al. 2015). The phtalate-related hypertension could be related to the increased plaque echogenicity and intima-media thickening and echogenicity that are more likely to happen in subjects exposed to phtalates (Lind and Lind 2011). In the study performed by Lind et al. (2011), MMP was related to the development of carotid plaques in an inverted U-shaped manner while MiBP and MMP levels were associated with the echogenicity of the plaques.

The current evidence on the association between phtalates and cardiovascular risk factors is of little–high quality. This is due to the fact that phtalates have short physiologic half-lives; thus, the single measurement performed in most of the studies cannot provide information on long-term exposure. Further, since phtalates have a large number of metabolites and the investigators that conducted studies on phtalates measured not the effects of the same metabolites, it is hard to get a comparison of the results across the studies. Moreover, the majority of the studies are based upon population-based surveys or pharmacovigilance studies, i.e., studies that were not designed to address the effect of phtalates on cardiovascular risk factors.

In summary, we conclude that the design of the studies and exposure assessment limitations make hard to get definitive conclusions on the effect of phtalates on cardiovascular health. Due to the short half-lives of phtalates, longitudinal studies assessing the relation between repeated measures of phtalate exposure and repeated health follow-up may provide insightful evidence about the effect of phtalates exposure on cardiovascular health.