Invited Perspective: Phthalates and Blood Pressure: the Unknowns of Dietary Factors.

Elevated blood pressure (also known as hypertension) remains the leading cause of stroke, cardiac disease, and end-stage renal disease as reviewed by Mills et al. (2020). Environmental chemicals have emerged as important cardiovascular risk factors (reviewed by Cosselman et al. 2015). Essential hypertension is a polygenic disorder that results from the interaction of environmental determinants and susceptibility genes (Singh et al. 2016). Diet has a well-known influence over blood pressure (Appel 2017), a relationship that has expanded to include not only foods themselves but also potentially hazardous chemicals, such as phthalates, that are found in food contact materials (Lu et al. 2018).

Phthalates are manmade chemicals used in the manufacture of food packaging, plastics (e.g., added to polyvinyl chloride products as a softener), personal care products (e.g., perfumes, deodorants, shampoo), and pharmaceuticals (Hubinger and Havery 2006). Human exposure to phthalates can occur through ingestion, inhalation, skin absorption, and intravenous injection. Once absorbed, phthalates are converted to their respective metabolites and excreted; hence, they do not accumulate in the human body (CDC 2021). Experimental studies have shown that prenatal exposure to phthalates is associated with alterations in vascular function in the offspring, such as endothelial dysfunction (Rahmani et al. 2016), oxidative stress (Rahmani et al. 2016), up-regulation of angiotensin II type 1 (Lee et al. 2016) and endothelin-1 (Jaimes et al. 2017) receptors, and abnormalities in adrenal function (Qian et al. 2020), all of which could affect blood pressure regulation and lead to hypertension (Lu et al. 2018).

Blood pressure is controlled by the action of redundant systems, including regulatory cross-talk among genetic factors and vasoactive pathways in response to changing environmental conditions (Arenas et al. 2013). Cardiovascular adaptations to pregnancy are a good example of this dynamic interaction. In pregnancy, total blood volume increases 20–100% above prepregnancy levels (Sanghavi and Rutherford 2014). In order to accommodate this large increase in circulating volume, vasodilation and reduction of the systemic vascular resistance start early in the first trimester (Sanghavi and Rutherford 2014). Consequently, blood pressure levels decrease in the first trimester to a nadir during the second trimester and gradually increase during the third trimester to reach preconception levels postpartum (Sanghavi and Rutherford 2014; Meah et al. 2016). The reduction in vascular resistance seen in pregnancy is associated with a decrease in the pressor effects of vasoconstrictors, such as angiotensin II and norepinephrine (Benjamin et al. 1991), and an increase in vasodilators, such as nitric oxide and prostacyclin (Cockell and Poston 1997). These changes occur in response to humoral agents such as estrogen, progesterone, and other pregnancy neuroendocrine factors still under investigation (Hagedorn et al. 2007). Interference with these physiological changes may lead to hypertensive disorders of pregnancy, postpartum hypertension, or both (reviewed by Sankaralingam et al. 2006; Katsi et al. 2020).

In a new study, Wu et al. (2021) investigated the association of prenatal exposure to phthalates with blood pressure during the third trimester of pregnancy and up to 72 months postpartum, in a cohort of 892 pregnant women from Mexico City. Urinary levels of a mixture of 15 phthalate metabolites were measured during the second and third trimesters. The authors also identified postpartum trajectories for systolic (SBP) and diastolic blood pressure (DBP) through 72 months and tested for the probabilities of the overall and individual phthalates of being on those trajectories. They found that an increase in overall urinary phthalate mixture levels was associated with steeper SBP rise during mid-to-late pregnancy, higher postpartum blood pressure, and a lower probability of being in a decrease–increase postpartum trajectory for SBP and DBP, characterized by a sharp decrease in blood pressure 1–18 months postpartum followed by a steady long-term increase through 72 months postpartum. Intriguingly, the relationships with blood pressure differed by metabolite. For instance, higher urinary 2-ethylhexyl phthalate was associated with a trajectory of greater SBP rise during mid-to-late gestation but lower short- and long-term postpartum SBP. Similarly, higher urinary monobenzyl phthalate (MBzP) was associated with higher SBP and DBP during mid-to-late pregnancy, and lower short-term postpartum blood pressure, but it was not associated with blood pressure after 18 months. Conversely, mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) was not associated with mid-to-late pregnancy blood pressure, but it was associated with higher postpartum blood pressure.

The findings by Wu et al. (2021) indicate that phthalates may interfere with blood pressure regulation and that phthalates metabolites may act on different vasoactive pathways. Therefore, phthalates could have a distinct effect on blood pressure levels. These findings may explain the different results in prior studies relating phthalates metabolites with either high (Werner et al. 2015) or low (Warembourg et al. 2019) blood pressure. These observations by Wu et al. (2021) merit further exploration at both the physiological and the epidemiological levels. For instance, it remains unclear if phthalates are associated with any of the clinical phenotypes of hypertension, such as pregnancy-induced hypertension, preeclampsia, or postpartum hypertension.

An important limitation of the study by Wu et al. (2021) is the lack of repeated urinary levels of phthalates postpregnancy. Phthalates are rapidly excreted (Wang et al. 2019), and their urinary metabolite levels may vary over time within an individual. Thus, urinary levels during pregnancy may not correlate with long-term exposure patterns (e.g., after 72 months postpartum). However, phthalate exposure may be relatively constant given these chemicals’ ubiquitous presence in food packaging and personal care products (Wittassek et al. 2007). Moreover, the impact of any interaction or confounding of phthalates with major dietary determinants of blood pressure (e.g., sodium, potassium, calcium, caloric intake) is unclear and was not evaluated in the study by Wu et al. (2021).

As reviewed in a meta-analysis by Goodman et al. (2014), the association of phthalate metabolites and obesity parameters may be confounded by covariation of body weight and dietary composition (e.g., processed vs. unprocessed foods) and phthalate exposure. Thus, women with higher blood pressure during or after pregnancy may have experienced higher weight gain, higher caloric and sodium intake, and higher phthalate exposure (e.g., from processed foods). In fact, in the study by Wu et al. (2021). the association of MECPTP with postpartum blood pressure was attenuated by the addition of body mass index to the statistical model.

In conclusion, the study by Wu et al. (2021) opens new avenues for research on the role of environmental exposures and blood pressure levels, specifically on the effect of phthalates on pathways regulating blood pressure. The authors used an elegant statistical strategy for the analysis of blood pressure changes after pregnancy in a relatively large cohort of pregnant women. Their study provides further evidence that the exposure to synthetic chemicals in food contact materials may result in alterations on cardiovascular function.