Parabens (p-hydroxybenzoate) are a family of compounds with phenolic groups, mainly including methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), and butyl paraben (BuP) (Fisher et al., 2020). Parabens have unique antibacterial properties with relatively low prices, hence they have been widely applied as antimicrobial preservatives and aromatics in various consumer products, such as food and beverages processing, personal care products, and drugs, for more than 90 years (Bledzka et al., 2014, Fisher et al., 2017, Snodin, 2017). Humans can be exposed to paraben in many ways, including cosmetics (Bledzka et al., 2014), diet (Zhao et al., 2021), indoor dust (Wang et al., 2012), and drinking water (Ferreira et al., 2011). The frequent detection of paraben in the blood (Li et al., 2020) and urine (Jurewicz et al., 2020) also verifies the high exposure of humans to this substance.
In 2008, Cosmetic Ingredient Review and US Food and Drug Administration conducted safety assessments on the use of parabens and concluded that their use in cosmetics was safe (Andersen, 2008, Fisher et al., 2017). However, parabens have long been considered as endocrine disruptors, and their estrogenic activities increased with the increase of the alkyl substituent length (Han and Washington, 2005). Moreover, parabens could cause a wide range of adverse health effects on animals and humans, such as significantly lower sperm counts and testosterone levels in rats (Kang et al., 2002, Oishi, 2001), decreased body weight and height in children (Wu et al., 2019), and decreased serum thyroid levels in humans (Aker et al., 2018). Hence, European Union imposed restrictions on the use of parabens in cosmetics from the year of 2009 (i.e., < 0.4% for single and < 0.8% for mixtures of parabens) (Zhu et al., 2020). China is the second-largest consumer of cosmetics in the world (Song et al., 2020), paraben exposure may pose a health risk to the Chinese population.
To date, there have been many studies on the association of paraben with immune diseases, most of which have focused on sensitive populations such as mothers and infants or children. For example, an epidemiologic study on 587 pregnant women in France suggested that exposure to EtP was correlated with the increased rate of asthma (Vernet et al., 2017). Only one study from the United States explored the relationships of paraben with adult autoimmune diseases, which reported that urinary MeP, PrP, EtP, and BuP levels were negatively associated with inflammatory bowel disease in people aged 20–80 years (de Silva et al., 2017). Therefore, studies between paraben and adult autoimmune diseases in China are still lacking. Rheumatoid arthritis (RA), a systemic heterogeneous autoimmune disease, is characterized by symptoms such as joint destruction (Yarwood et al., 2016, Zeng et al., 2017). Some studies claimed that 0.5 to 1.0% of adults worldwide are affected by this disease (Tian et al., 2021). Although information on demographic trends in the prevalence of RA is scant, concern exists that there may be an increased risk of developing RA due to the increasingly frequent exposure to organic pollutants in the environment. The underlying pathogenic mechanism of RA is considered to be a disturbed immune response inducing increased susceptibility in the host in response to single or multiple environmental risk factors. Rheumatoid factors (RF), anti-cyclic citrullinated peptide antibody (ACPA), C-reactive protein (C-RP), and erythrocyte sedimentation rate (ESR) are commonly used as diagnostic markers of RA. Watkins et al. (2015) explored the relationship between paraben exposure and markers of oxidative stress and inflammation and reported that BuP concentrations were associated with C-RP levels. Therefore, it is necessary to quantify the parabens residuals in serum and to determine the relationship between RA and parabens exposure in humans.
Serum is one of the major matrix used for human biological monitoring studies (Angerer et al., 2007). Indicator values related to RA, including ACPA, RF, C-RP, ESR, and immunoglobulin G (IgG), are also determined in the human serum. Although parabens in the human body have a short half-life of about 24 to 72 hours, parabens can still be detected in human serum and blood samples (Boberg et al., 2010, Janjua et al., 2008). A domestic biomonitoring study has suggested that the detected frequencies of MeP, EtP, PrP, and BuP in young adult blood were 82%, 57%, 77%, and 41%, respectively (Zhang et al., 2020). Moreover, paraben exposure is widespread in different populations from various countries (Adoamnei et al., 2018, Iribarne-Duran et al., 2020, Vela-Soria et al., 2013).
In the present work, we established a case-control cohort, including 152 RA cases and 138 controls, and collected their whole blood samples in Hangzhou, China. Four parabens, including MeP, EtP, PrP, and BuP, were quantified in these serum samples. The main purposes of this study were to determine the profile of target parabens in human serum and to explore the relationship among paraben levels in human serum, immune markers, and incidence of RA by adjusting the covariates. This study contributes to our better understanding of the risk of human immunotoxicity from exposure to parabens.