Urinary phthalate metabolites mixture, serum cytokines and renal function in children: A panel study

Highlights

• The panel study firstly explored link of phthalate metabolites mixture with children’s renal function.

• Urinary phthalate metabolites were dose-responsive related to eGFR reduction.

• MEP of phthalate metabolites mixture was the major contributor for decreased eGFR.

• eGFR related phthalate metabolites were linked with increased multiple cytokines.

• CCL27 and CXCL1 might partly mediate the association of MEP with eGFR.

Abstract

Epidemiological evidence regarded the relations of phthalates with children’s renal function and its underlying mechanism were largely unknown. We conducted a panel study using 287 paired urine-blood samples by repeated measurements of 103 children (4–13 years) across 3 seasons to explore effects of urinary phthalate metabolites on estimated glomerular filtration rate (eGFR) and the potential role of multiple cytokines. We found that mono-ethyl phthalate (MEP), monobutyl phthalate (MBP), mono-benzyl phthalate (MBzP) and mono-n-octyl phthalate (MOP) were significantly associated with eGFR reduction. Compared with the lowest quartile, MBP, MBzP and MEP in the third and fourth quartiles exhibited a graded decrease in eGFR. Meanwhile, weighted quantile sum regression analyses showed an inverse association of metabolites mixture with eGFR, to which MEP, MBzP, MOP were the major contributors. MEP also remained robust in multiple-phthalate model. Age and weight status might modify such relationships with significant interactions. Furthermore, eGFR related phthalate metabolites were associated with increased multiple cytokines, and CCL27, CXCL1 might be potential mediators between MEP and eGFR with mild mediated proportions. Accordingly, urinary phthalate metabolites were related to eGFR reduction in dose-response manner and multiple cytokines elevation, of which CCL27 and CXCL1 might partly mediate phthalate-associated decreased renal function among children.

Introduction

Phthalates, as widely used plasticizers, have been applied for consumer and industrial products, including personal care products, food packaging, furnishings, nutritional supplements, medical devices, and children’s toys (Andaluri et al., 2018, Wang et al., 2018, Xu et al., 2020). The consumption of phthalates has increased about 21% over last five years, and mainly concentrated in Asia-Pacific region (Benjamin et al., 2017). Due to its thermal instability, phthalates might be penetrated into human body via air inhalation, digestive intake, and dermal absorption. Although its half-lives in the body is quite short within several hours (Anderson et al., 2011), general population continuously exposed to phthalates almost everyday. Growing number of studies showed that phthalate metabolites could exert great toxicity on endocrine metabolism, reproductive system and so on (Hyland et al., 2019, Kahn et al., 2020, Mariana et al., 2016). Notable, experimental study observed the metabolic hydrolysates of phthalates preferred to be excreted by urine (Wang et al., 2019), which inevitably caused damage to the kidney.

Several cross-sectional studies found that urinary phthalate metabolites were related to increased urinary albumin-to-creatinine ratio, microalbumin, and reduced estimated glomerular filtration rate (eGFR) in adults (Chang et al., 2020, Chen et al., 2020, Chen et al., 2019b, Chen et al., 2019a, Lee et al., 2020). Compared to adults, children are more likely to expose to phthalate on account of their hand-to-mouth behavior and sensitive respiratory system (Benjamin et al., 2017). However, limited evidence available on the associations of phthalates and children’s renal function came out with inconsistent results. Cross-sectional studies observed the positive relation of di-(2-ethylhexyl) phthalate with albumin-to-creatinine ratio in general children (Trasande et al., 2014, Tsai et al., 2016), and eGFR was decreased in response to high-molecular-weight phthalates but increased by low-molecular-weight phthalates in children with chronic kidney disease (Malits et al., 2018). Whereas other cross-sectional studies (Chang et al., 2020, Chen et al., 2019a) and only one longitudinal study (Jacobson et al., 2020) showed no significant effect of phthalate metabolites on eGFR among children and adolescents. More importantly, phthalate metabolites usually were exposed as a mixture of several highly correlated chemicals, while these previous studies only considered nephrotoxicity of each single phthalate metabolite rather than phthalate mixture. And which specific phthalate metabolite contributing to the nephrotoxicity is still unclear.

Recently, a systematic review based on 29 observational epidemiologic studies reported the positive association of phthalates exposure with oxidative stress, while it’s uncertain for its relation with inflammation (Sweeney et al., 2019). Prior experimental studies in vivo observed exposed to phthalates could result in significant increase of oxidative stress and cytokines in supernatant of kidney (Chen et al., 2019a, Chen et al., 2019b, Gu et al., 2021) and systemic inflammation (Campioli et al., 2014). Nevertheless, population-based evidence of mechanisms underlying associations between phthalates and renal function remained largely unknown.

Further, it’s reported that eGFR estimated by serum creatinine was superior to urinary albumin-to-creatinine ratio and blood urea nitrogen (BUN) (Weintraub et al., 2015, Colombo et al., 2020) and regared as the most useful biomarkers (Levey and Inker, 2017) to reflect renal function. Therefore, we conducted a longitudinal panel study to explore the effect of urinary phthalate metabolites, either as individual or a mixture, on eGFR, and the possible role of serum cytokines in association of phthalate metabolites with eGFR among healthy children.