Organophosphate flame retardants (OPFRs), a class of thermally stable organic compounds that contain phosphorus, have been extensively employed as flame retardants and plasticizers in a variety of commercial products, including textiles, electronics, building materials, furniture, lubricants, varnishes, and varnishes (Huang et al., 2022; Yang et al., 2019). Following the phase-out of polybrominated diphenyl ethers (PBDEs), OPFRs have emerged as the prevailing alternative flame retardants.

China is a major producer and consumer of OPFRs, with estimated annual emissions of approximately 30,000 tons (Zhao et al., 2022). Surprisingly, 201 out of 367 factories producing OPFRs around the world were located in mainland China as of 2020 (Huang et al., 2022). Since OPFRs are non-covalent additives in products, they possess volatility, allowing them to migrate into the environment during the production, disposal, usage and recycling processes, leading to the contamination of the air, water, soil and organisms (Greaves and Letcher, 2017; Liu, Y.X. et al., 2021; Stapleton et al., 2009; van der Veen and de Boer, 2012). As a result, humans are widely exposed to OPFRs through diet, inhalation, and dermal contact (Gbadamosi et al., 2021; Kim and Kannan, 2018; Kurt-Karakus et al., 2018; Ma et al., 2021; Percy et al., 2020a). Assessments of urinary OPFR metabolites have shown that pregnant women in several cities in China, including Dalian, Wuhan, and Shanghai, are widely exposed to OPFRs (Chen et al., 2019; Chen et al., 2023; Feng et al., 2016; Li et al., 2021; Liu et al., 2021, Liu et al., 2021, Liu et al., 2021; Luo et al., 2020; Luo et al., 2021; Yao et al., 2021; Zhao et al., 2021). Moreover, studies have reported the presence of OPFRs in the placenta, decidua, chorion, and amniotic fluid of pregnant women in China (Bai et al., 2019; Ding et al., 2016; Zhao et al., 2017). Multiple studies have provided evidence of the detrimental effects of OPFRs on human health, particularly in pregnant women and their offspring, including reproductive toxicity, preterm birth, allergic diseases, and blood pressure disorders (Li et al., 2023; Luan et al., 2023; Luo et al., 2020, 2021). Additionally, OPFRs have been shown to have the potential of maternal-fetal transfer, putting developing fetuses at risk of exposure (Bai et al., 2019; Ding et al., 2016; Zhao et al., 2017).

Fetuses and children are highly susceptible to neurotoxic damage from exogenous chemicals due to their rapid structural and functional brain development, especially during the first two years of life (Rice and Barone, 2000). Animal and cellular experiments have indicated that OPFRs have the potential to induce neurotoxicity through various mechanisms, including interference with glutamate and gamma-aminobutyric acid regulation, disruption of endocrine metabolism, disturbance of thyroid hormone homeostasis, induction of oxidative stress, triggering microglia-mediated inflammation, as well as modulation of gene and protein expression (Bamai et al., 2019; Dishaw et al., 2011; Patisaul et al., 2021; Wang et al., 2020, Wang et al., 2020; Wang et al., 2015; Xu et al., 2015; Zhong et al., 2020). Therefore, it is imperative to conduct thorough investigations in order to assess the potential adverse health risks associated with prenatal exposure to OPFRs and their impact on neurodevelopment during early life.

To date, a limited number of epidemiologic studies have investigated the potential link between maternal OPFRs exposure and childhood neurodevelopment. Among these studies, six were conducted in the United States and Europe, while only one was carried out in China. It is challenging to compare the results from these studies as they vary in terms of the OPFR exposures, the age groups of children, and the methods of neurodevelopment assessment. Two independent studies in the United States and Norway have both reported a significant association between exposure to diphenyl phosphate (DPHP) and the occurrence of attention deficit hyperactivity disorder (ADHD) as well as attention deficit in children (Choi et al., 2021; Doherty, B. T. et al., 2019b). Two additional independent studies conducted in the United States have documented that prenatal exposure to OPFRs was linked to decreased levels of intelligence and working memory in children at the age of seven, but not at age eight (Castorina et al., 2017a; Percy et al., 2021b). The findings from Liu et al. and Doherty et al. provide compelling evidence for the need to investigate the effect of maternal OPFR exposure on neurodevelopment in younger children, which all revealing a significant correlation between maternal exposure to organophosphate esters and cognitive function or neurodevelopmental levels in children aged 2–3 years (Doherty et al., 2019; Liu, W.Y. et al., 2021). It is noteworthy that the majority of aforementioned studies have primarily concentrated on the impact of individual chemicals, disregarding the fact that individuals are typically exposed to multiple chemicals simultaneously. This simultaneous exposure can result in interactions between the chemicals, further complicating their effects (Lee et al., 2021; van den Dries et al., 2021; Zhang, S.Y. et al., 2022; Zhang, Y.Q. et al., 2019). Therefore, researchers increasingly advocate for the investigation of the combined effects of prevalent environmental pollutants (Tanner et al., 2020). Given the intricate exposure patterns, potential high correlations among chemicals, and complex interactions within the environmental chemicals, a suitable mixture analysis is necessary to accurately assess the overall effects of multiple pollutants. Moreover, there is currently no literature available that evaluates the effects of maternal OPFR exposure on the neurodevelopment of children around the age of 1, without considering that neurodevelopmental effects observed in early infancy might better reflect intrauterine exposure, as they are less likely to be influenced by postnatal factors that could affect the results in childhood (Park et al., 2016).

The present study was carried out at the southern coastal region of the Laizhou Wan (Bay) located in the Shandong Province of China (LWBC). China's OPFR production factories are mainly located in Shandong, with Weifang being the main area that accounts for highest number of factories (16 factories out of 48 in Shandong) producing OPFRs (Huang et al., 2022). Given the widespread distribution of OPFRs in various environmental media and the high pollution levels of OPFRs in this city, it is important to specifically focus on OPFRs exposure of people in this city (Ma et al., 2017).

Therefore, the objective of this study was to examine the potential connections between prenatal exposure to seven specific metabolites of OPFRs and their combined effects of mixture on the neurodevelopment of 12-month-old infants using multivariate linear regression and weighted quantile sum (WQS) regression models based on a prospective cohort including 270 mother-infant pairs from LWBC, China.