Polychlorinated biphenyls (PCBs) are a class of synthetic organic compounds, which contain 209 congeners (1). Based on their three-dimensional structure, PCBs can be divided into two main categories: Dioxin-like PCBs (DL-PCBs) and non-dioxin-like PCBs (NDL-PCBs). Owing to their chemical and thermal stability, PCBs were used widely in various industrial and commercial applications, including lubricating oils, plasticizers, hydraulic fluids, paint and ink (2-4). Commercial production of PCBs began in 1929 in the United States and were sold worldwide as commercial mixtures, such as Aroclor^®, Clophen^® and Phenclor^® in the 20th century before stopping in the late 1970s (1,5,6). PCBs are often used in long-life products, with some reaching >30 years, such as capacitors and sealants (7). For the PCBs used in closed electrical systems, large release of chemicals do not occur as long as the electrical equipment remains intact during use or storage; however, significant release may occur if these systems are not properly managed during the waste and recovery phases (8). Persistent PCB emitters are likely to be released continuously and/or intermittently over the next few decades (9). The non-degradable property of PCBs makes them persistent organic pollutants, which exist in food chains, water, soil and even in air circulation (2,10).

In 1992, Hales and Barker (11) proposed the concept of developmental origins of health and disease, which is a hypothesis describing the fetal basis of adult disease. As of late, it has been widely accepted that early lifetime exposure to environmental endocrine disrupting chemicals (EDCs) could affect the long-term susceptibility of offspring to disease (12,13). Intrauterine development is a critical period of plasticity for most organs and systems, wherein the fetus changes the structure and function of its organs, which is known as 'programming', to prepare for improved extrauterine survival (12). Neurodevelopment, one of the most fragile processes, which occurs from the embryo to adolescence, is sensitive to environmental insults. Delayed neurotoxicity can develop even years after discontinuation of the adverse exposure (14). Using structural MRI and functional MRI, intrauterine PCB exposure was found to increase cortical thickness over the right inferior parietal lobule in 30-year-old men, suggesting long-term effects on brain plasticity and compensatory neuropsychological performance (15). Prenatal exposure to a variety of environmental EDCs can cause fetal epigenetic disorders and neurodevelopmental defects, which may induce subsequent developmental disorders and diseases (16-18). A growing number of epidemiological studies conducted worldwide demonstrated the association between perinatal PCB exposure and neurobehavioral effects, including cognition (19,20), intelligence (21), hearing (22), behavior (20) and autism (23); however, these epidemiological investigations have not yielded consistent results, and the epidemiological differences and the underlying mechanisms have not been described in detail.

Therefore, the PubMed MEDLINE electronic database (https://www.ncbi.nlm.nih.gov/pubmed) was searched using 'polychlorinated biphenyl', 'neurological', 'nervous', 'gestational', 'prenatal' and 'intrauterine' as key words from the last two decades (2001-2020) and a total of 129 articles were retrieved. After excluding non-English and irrelevant articles, 78 articles were used. The key aim of the present review was to systematically analyze the epidemiological differences and describe the possible mechanisms of intrauterine PCB exposure on the development of the nervous system, which will further the understanding of life-long neurotoxic effects following developmental exposure to PCBs.

PCBs can accumulate in biota and biomagnify using food webs (24,25). Due to global fractionation, PCBs migrate in the atmosphere, and accumulate even at high latitudes and remote areas (26). Their toxicity can be amplified through bioaccumulation in grassland food networks. In a study of closed-loop food webs in Inner Mongolia (27), the biological amplification of PCBs in mice to snakes was found to be >1,000 times, suggesting that the relatively low concentrations and low toxic equivalent concentrations at the bottom of the food chain are biomagnified at high trophic levels. Various studies have demonstrated that fish products are the main source of PCBs, and that their PCB content varies with the region and type of fish, while grains and vegetables contain fewer PCBs (28-31). However, fish consumption in the general population is relatively low, suggesting that the health risks associated with exposure to PCBs have a certain tolerable daily intake (30). Maternal socioeconomic indicators may be another possible risk factor for PCB accumulation (32), as low-income households may eat fewer fish and have less access to PCBs from fish.

Maternal PCB accumulation can be transferred to the offspring via the placenta and breast milk (33,34). For the mother, breastfeeding is the main method of excreting PCBs, while for the offspring, it is the main source of PCB accumulation. Takagi et al (33) used (¹⁴C)PCBs to investigate the association between maternal and progeny PCBs via intragastric feeding in a rat model. In the fetus, the highest PCB concentration was in the fetal placenta, followed by the liver, heart, skin, muscles, blood, lungs and the brain. In suckling offspring, the highest concentration was found in the adipose tissue, while intermediate concentrations existed in the skin, adrenal gland and the liver. The concentration of PCBs in the fetal blood [0.24 parts-per million (ppm)] was similar to that in the maternal blood (0.26 ppm) and was much lower compared with that in the milk (1.84 ppm). Furthermore, the PCB content in nursing rats was significantly lower compared with that in pregnant and virgin rats. However, exposure to PCBs in multiple pregnancies was not lower compared with that in the first pregnancy. The levels of PCBs in the maternal body and breast milk was associated with age, diet, parity, self-nutrition during pregnancy and smoking habits (35,36). The concentration of PCBs was reduced by previous lactation; however, older parturients could accumulate PCBs for longer periods of time. In contrast, younger mothers exhibited a shorter lifetime exposure to environmental pollutants (37).

Language is considered as an indicator of a child's cognitive development and language retardation may be the earliest sign of one or more neurodevelopmental disorders (38,39). Furthermore, in a cohort study, with a large group of mother-child pairs, high exposure to DL-PCBs during pregnancy increased the risk of language delay at age 3 years according to the parental report and Ages and Stages Questionnaire (40). However, due to the neurotoxicity of methylmercury, the neurotoxic effects of PCB cannot be assessed when individuals are exposed to both methylmercury and PCB (41).

Intrauterine PCB exposure could have a long-term impact on intellectual function. The effects of PCBs on intelligence seem to vary with age. Negative effects could develop or progress over time. A study by Berghuis et al (42) analyzed the association between the blood concentration of PCBs in pregnant women in the second and/or third trimester and intelligence using Touwen examination. They found that higher gestational exposure to several PCBs was positively associated with neurological functioning in 3-month-old babies. In addition, an early study revealed no statistically significant association between perinatal exposure to PCBs and the abilities of the children at 3-5 years, which were examined using the McCarthy Scales (43). However, as children become older, the negative effects of PCB on intelligence are becoming more notable (21,44,45). Lower levels of PCBs might be associated with higher intelligence in infants by stimulating the neuronal and/or hormonal processes, which leads to positive effects, while higher exposure levels might exert negative effects (42), suggesting the effects were dose-dependent. This is consistent with the way PCBs are transferred from the mother to the offspring. Since breastfeeding is the primary source of PCB exposure for newborns, from their mothers, it is possible that breastfeeding children have higher PCB accumulation (33).

It remains controversial whether cochlear function is immature in the first few months of human life or whether perinatal PCB exposure affects the auditory function in children. A collaborative perinatal project in the United States (22) suggested no association between PCB levels in serum from pregnant women and sensorineural hearing loss (based on hearing threshold) in 8-year-old children. Conversely, in fish-eating populations of the Faroe Islands, higher PCB content in the cord tissue was associated with increased hearing thresholds in infants (46). Jusko et al (47) found that PCB-153 concentrations in the maternal and cord serum were not associated with distortion product otoacoustic emissions (DPOAEs) in 45-month-old children, while high levels of PCB-153 in the serum from children at 6, 16 and 45 months were associated with poor DPOAE amplitudes, suggesting that continued PCB exposure was more harmful to auditory function compared with that for a specific period of exposure.

Behavioral problems are also symptoms or signs of neurodevelopmental abnormalities, including externalizing and internalizing behavior problems (48). Internal behavior problems, defined as a lack of control of emotions, seem to be more easily affected by prenatal PCB exposure. Conversely, parental child-rearing attitudes around the birth order may play a more important role in child behavior compared with that in prenatal PCB exposure itself (49). Meanwhile, epidemiological investigations have not revealed a potential association between PCBs and externalizing behavior problems, which include oppositional, hyperactivity and aggressive behaviors according to Behavioral Assessment System for Children-2 at age 8 years (20). Several studies using zebrafish, an ideal model for toxicological research, have confirmed that embryonic exposure to PCBs was associated with anxious behavior and altered reactions to visual threats (50-52).

Autism, also known as autism spectrum disorder (ASD), is a type of neurodevelopmental condition characterized by different degrees of impaired social interaction and communication, repetitive or stereotypic behaviors, narrow interests, and abnormal perceptions (53). The etiology of ASD has not been fully elucidated; however, a previous study has shown that PCB exposure alters the endogenous axis and hormone-dependent neurodevelopment, thereby increasing the risk of ASD (53). However, such associations have not been unanimously supported in all literatures. Granillo et al (23) enrolled high-risk cohort families, with at least one child with ASD and planned to have another baby. They found that there was no significant association between total PCBs and ASD. Furthermore, DL-PCBs decreased the risk of ASD with borderline significance, whereas NDL-PCBs significantly elevated the risk of ASD. In another study, which included 546 mother-infant pairs, in a pregnancy and birth cohort, there was no association between 6 PCB congeners (PCB118, PCB138, PCB158, PCB170, PCB180 and PCB187) in the maternal serum in the first trimester of pregnancy and ASD in their children at 3-4 years of age (54).

The effects of prenatal exposure to PCBs on offspring shows large interindividual variability. This inconsistency in epidemiological investigations may be attributable to a number of reasons, described below.

The possible mechanisms of PCB on the development of the nervous system are described in Fig. 1. The toxicological mechanism of DL-PCBs has been associated with the activation of AhR (60,71), while NDL-PCBs have been associated with RyR-mediated calcium (Ca²⁺) ion channels (72,73). Both DL- and NDL-PCBs may damage the fetoplacental unit (74,75), alter gene expression (76) and epigenetics (77), and affect neuroendocrine function (78).

PCBs are persistent environmental EDCs, and have environmental impacts, even though they have been banned for decades. There are still limitations with respect to understanding of PCB neurotoxicity. The novelty of the present review firstly systematically analyzed prenatal PCB exposure, particularly that gestational exposure affected the development of the nervous system in the offspring and even had long-term effects on the brain. Due to multiple contradictory factors, such as different types of PCB exposure, different exposure doses, different follow-up ages, and individual genetic susceptibility, there is not a consistent conclusion from epidemiology research. The relevant reasons of epidemiological investigation were analyzed, providing areas of future epidemiological investigations on intrauterine PCB exposure. The underlying mechanism of different PCBs congeners, including the activation of AhR, via RyR-mediated Ca²⁺ ion channels, and the epigenetic changes that can occur have been discussed; however, further investigation is required to fully understand the mechanisms involved. Furthermore, there is still no effective method to intervene or block the neurotoxicity of PCBs; therefore, the establishment of an ideal animal model is important. Despite these limitations and challenges, increasing attention should be made to PCB environmental pollution to avoid the potential adverse effects in the offspring.