Open Access

Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)

  • Authors:
    • Yinfeng Wang
    • Changchang Hu
    • Tao Fang
    • Yang Jin
    • Ruijin Wu
  • View Affiliations

  • Published online on: June 14, 2021     https://doi.org/10.3892/ijmm.2021.4983
  • Article Number: 150
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The developmental origins of health and disease concept illustrates that exposure in early life to various factors may affect the offspring's long‑term susceptibility to disease. During development, the nervous system is sensitive and vulnerable to the environmental insults. Polychlorinated biphenyls (PCBs), which are divided into dioxin‑like (DL‑PCBs) and non‑dioxin‑like PCBs (NDL‑PCBs), are synthetic persistent environmental endocrine‑disrupting chemicals. The toxicological mechanisms of DL‑PCBs have been associated with the activation of the aryl hydrocarbon receptor and NDL‑PCBs have been associated with ryanodine receptor‑mediated calcium ion channels, which affect neuronal migration, promote dendritic growth and alter neuronal connectivity. In addition, PCB accumulation in the placenta destroys the fetal placental unit and affects endocrine function, particularly thyroid hormones and the dopaminergic system, leading to neuroendocrine disorders. However, epidemiological investigations have not achieved a consistent result in different study cohorts. The present review summarizes the epidemiological differences and possible mechanisms of the effects of intrauterine PCB exposure on neurological development.

1. Introduction

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.

2. Bioaccumulation of 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).

3. Exposure to PCBs during pregnancy and progeny nervous system development

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).

4. Analysis of epidemiological differences

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.

Genetic susceptibility

Genetic polymorphism refers to the presence of two or more alleles, at a particular locus. Depending on the allele and the gene, these polymorphisms may either protect the individual from pesticides-induced oxidative damage, or conversely, makes its more vulnerable (55,56). For example, two important polymorphisms (Q192R and L55M) in the human paraoxonase 1 (PON1) gene, a hydrolytic enzyme, which protects the toxicity of organophosphates insecticides, have opposing roles. The PON1 Q192R polymorphism enhanced the role of PON1, while PON1 L55M was hypothesized to have the opposite effect (57). Cytochrome P450s (CYPs) plays a key role in detoxification or activation of numerous xenobiotics (55). DL-PCBs bind and activate the aryl hydrocarbon receptor (AhR) to regulate three members of the CYP family: CYP1A1, CYP1A2 and CYP1B1 (58), which play an important role in the detoxification of PCB (59).

Poor-affinity AhRs and high protein levels of CYP1A2 in maternal liver cells provided important protection to the offspring against the sensitivity to gestational PCBs exposure (60-62). Conversely, high-affinity AhRs were found to respond to low levels of DL-PCBs, while the CYP1A2-mediated detoxification pathway could sequester DL-PCBs to prevent transfer to the offspring (60). The affinity of AhR and the expression of CYP1A2 in the liver varies in the population, which indicates that there are large individual differences in the susceptibility to PCBs (63).

The toxicological effect of NDL-PCBs has been associated with the ryanodine receptor (RyR). Compared with that in wild-type mice, double mutant (functional mutation in the RyR1 and a human CGG repeat expansion in the fragile X mental retardation gene 1) mice were more susceptible to PCBs. Perinatal exposure to PCBs in the maternal diet caused dysbiosis of the gut microbiota, resulting in behavioral deficits in the double mutant mice (64), which represents a potential role for protein digestion and microbial putrefaction in the gut-brain axis in patients with ASD (65).

Different PCB congeners have different effects and are dose-dependent

PCBs contain 209 homologous complexes and hydroxylated PCBs (OH-PCBs) (1). Due to the inconsistent homologues of PCB contamination in the environment, there are different epidemiological associations between PCB exposure during pregnancy and the nervous system in the offspring, even in the same study (23). On the other hand, gestational PCB exposure was found to be dose-dependent. The amount of PCB exposure in the environment is variable. As aforementioned, higher cord blood PCB concentrations were associated with a higher hearing threshold, indicating that there may be a threshold for prenatal PCB ototoxicity (22,46,47).

Inconsistent study environment and evaluation endpoints

Prenatal PCB exposure is usually detected in the maternal and umbilical cord blood, which may not be reflected in fetal suffering. In practice, cord blood is normally collected at birth, which does not include the sensitive window in early pregnancy associated with progeny health. Amniotic fluid provides another possible fetal environment, which can be analyzed, and amniocentesis is usually performed in the second trimester, during the prenatal diagnosis of advanced chromosomal abnormalities or fetal deformities (66,67). However, amniocentesis is an invasive procedure and is not used for routine prenatal examinations. Therefore, it is not realistic to use it for prospective studies.

Different evaluation endpoints are another reason for the uncertainty with respect to the different results of epidemiological studies, even within the same cohort. As aforementioned, the negative effects of PCBs exposure during pregnancy on the intelligence of the child became more pronounced with age (21,42,68). Furthermore, the age of the mother, education, race, preconception body mass index, fat mass, birth order, birth weight, number of pregnancies, duration of breastfeeding and diet, confound the effects of PCBs on the health of the offspring (69,70).

5. Mechanism of prenatal exposure to PCBs on offspring nervous system development

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).

DL-PCBs affect the development of the nervous system by activating AhR

AhR is a member of the eukaryotic Per-Ah receptor nuclear translocator (ARNT)-Sim domain protein family, which is located in the cytoplasm and binds to chaperone proteins hsp90, and co-chaperone protein p23 (79). Following ligand activation by DL-PCBs, the AhR separates and is translocated into the nucleus, where it binds to DNA response elements with an ARNT and begins transcription (71). In several animal models of development, AhR has been demonstrated to be widely distributed in the cerebral cortex, cerebellum, hippocampus and olfactory bulb neurons (80,81). Increasing evidence has also indicated that the neurotoxicity of prenatal exposure to DL-PCBs was associated with AhR activation in a dose-dependent manner (58,62,82), suggesting it plays an important role in neural development.

The following mechanisms may be involved in the effect of the DL-PCBs on the development of the nervous system via AhR: i) AhR might act as a common upstream regulatory molecule, that inhibits acetylcholinesterase (AChE) activity via transcriptional regulation of dioxin-response element sites in human AChE promoters and post-translational regulation of AChE-targeting microRNAs (83). AChE is an enzyme with high catalytic activity in the hydrolysis of acetylcholine, an important neurotransmitter. It not only plays a key role in regulating cholinergic neurotransmission, but is also an important enzyme in neurodevelopment (84); ii) DL-PCBs affect estrogen signaling via AhR, thereby reducing estrogen receptors and estrogen levels to disrupt the neuroprotective effect of estrogen in the cerebral cortex (83,85) and iii) over-activated AhR activity impairs neuronal migration during hippocampal development (86).

NDL-PCBs promote dendritic growth and alter neuronal connectivity via RyR-mediated Ca2+ ion channels

RyR is a Ca2+-regulated ion channel found in the sarcoplasmic reticulum (SR) in muscle cells and in the endoplasmic reticulum (ER) in non-muscle cells. Activation of RyR can rapidly release Ca2+ from the ER/SR to assist with neuronal network development and endocrine balance (72,87). A NDL-PCB and a single congener increased RyR activity 2.4-19.2 times (88). NDL-PCBs have been associated with neurogenesis, by enhancing the activity of the RyR (72).

Dendritic structure is a key determinant of neuronal connectivity (89). Synaptic connections shape neural circuitry during development and also underlies associative learning (90). The remodeling of the dynamic structure of dendrites during development is primarily driven by Ca2+-dependent signal transduction pathways triggered by external signals (91,92). NDL-PCBs promote dendritic growth and alter neuronal connectivity in the hippocampus and cerebellar Purkinje cells (73,93). Loss of neuronal connectivity is a common pathological feature of most neurodevelopmental disorders (94). Another developmental neurotoxicity of PCBs is caspase-dependent cell death in the hippocampal neurons via activation of the RyR and increased reactive oxygen species (95,96). Disturbances in the speed or amplitude of apoptosis in the developing hippocampus will change the number of cells, thereby changing the connectivity of neurons, and even leading to deficits in high-level function.

DL- and NDL-PCBs alter genetic and epigenetic information

Epigenetic markers are dynamic and can be affected by the environment, particularly during critical periods of embryonic development and early life (97). Several studies have highlighted the importance of parental exposure to PCBs, which could affect the epigenome of the offspring and the susceptibility of the offspring to disease (97-99). DNA methylation refers to the addition of a methyl group to DNA using the enzyme, DNA methyltransferase, which can regulate genetic expression without changing the DNA sequence (17). In early life, DNA methylation can be affected by environmental factors and can persistent even after removal of these factors (99,100). In primordial germ cells, DNA methylation decreased from 92% in post implantation embryos to 6.0% at week 10 in females and 7.8% at week 11 in males. DNA methylation levels gradually increased after 19 weeks until they reached the level of mature germ cells after birth (101). The placenta provides nutrients and oxygen to the fetus. It also contains an epigenome, which enables heritable and sustained changes to gene expression levels without altering the DNA sequence. The placenta remains hypomethylated at the genome level; however, site-specific epigenetic patterns are preserved (77). Imprinted genes are a subset of genes which undergo epigenetic programming during early development and also undergo remodeling during pregnancy, highlighting their potential sensitivity to environmental factors (102). Several studies have demonstrated that changes in placental DNA methylation were associated with environmental exposure (77,102-104). In a previous study, errors in maintaining epigenetic markers affected DNA methylation and was associated with an increased risk of developing ASD (105).

In zebrafish, developmental exposure to low levels of AhR agonist, PCB-126 upregulated genes associated with Ca2+ channels and downregulated genes associated with oxidative phosphorylation, suggesting that DL-PCBs could affect Ca2+ homeostasis in the brain in vivo, and one of the pathways directly affected by altered Ca2+ signaling was the MAPK signaling pathway (76). Both Ca2+ and MAPK signaling play important roles in neurodevelopment and cognitive functions, such as learning and memory (76,106).

PCBs disrupt neuroendocrine function

PCBs easily penetrate the placental and blood-brain barriers, resulting in PCB accumulation in the offspring's brain (107). Early exposure to dioxins and PCBs could alter basic cellular signaling processes and endocrine functions, thereby affecting the synthesis and activity of important neurotransmitters in the central nervous system, as well as the development of brain tissue (108,109).

Thyroid hormones, which regulate the migration and maturation of γ-aminobutyric acidergic interneurons, are crucial during fetal development, particularly in the nervous system (110,111). The disruption of this process causes the formation of abnormal neural circuits, which has been hypothesized to underlie some neurodevelopmental disorders in humans, such as ASD (112). In early pregnancy, the fetal thyroid hormone is completely dependent on transport from the mother prior to fetal self-synthesis (113). An increasing number of epidemiological studies have confirmed that gestational PCB exposure was associated with disturbances in the thyroid function of neonates (114-116). This destruction has long-lasting effects in the offspring, potentially lasting until the child is 8 years old (116). The effects of PCBs and OH-PCBs on thyroid function may involve the following mechanisms: i) PCBs may competitively bind to transthyretin, particularly OH-PCBs, which have stronger binding affinity compared with that in their parent compounds; ii) PCBs may interact with thyroxine receptors or suppress DNA transcription and iii) OH-PCBs inhibit thyroid hormone sulfation, affecting the peripheral metabolism of thyroid hormones (114,117).

Dopaminergic systems are another potential target of PCB exposure during critical periods of neuronal development. For example, DL-PCBs may elevate dopamine (DA) concentrations in the prefrontal cortex via an estrogenic effect and alter behavior (78). A coculture model of developing rat striatum and ventral mesencephalon (VM) revealed that the neural toxicity of PCBs increased neuronal cell death and reduced the number of DA neurons in the VM (118). PCBs disturb DA transport into vesicles in the presynaptic terminal by inhibiting the activity of the DA transporter and vesicular monoamine transporter 2, leading to an accumulation of unsequestered DA, and increased production of the DA metabolites, which results in free-radical formation and caspase-mediated neuronal cell death (118,119).

PCBs damage the fetal placental unit

The fetal placental unit connects maternal and fetal circulation and plays an important role in nutrient metabolism and endocrine systems (120). Lipophilic EDCs can accumulate in the placenta and can damage the fetoplacental unit and affect placental endocrine function (121,122). Angiogenesis, in the fetoplacental unit, is the result of cross-communication between different cells, such as invading trophoblasts, endothelial cells and specialized natural killer cells (119). The binding of δ-like (Dll)-4 to Notch receptors induces the proteolytic release of the Notch intracellular domain and regulates VEGF expression, forming a primary vascular network and secondary angiogenesis at the maternal-fetal interface (123,124). The Dll4-Notch4-VEGFR2 signaling axis is a potential target for PCBs, particularly when the IL-10 gene is knocked out, which leads to poor spiral artery remodeling and reduced angiogenesis in the placenta (74). Animal studies have shown that gestational PCB126 exposure leads to some histopathological changes in the placental tissue, which manifests as hyperemia, hemorrhage, degeneration, apoptosis in the labyrinth layer and spiral arteries of the placenta, resulting in fetal hypothyroidism and endocrine disruption. The presence of hypothyroidism negatively affected the fetal pituitary thyroid axis, the growth hormone/insulin-like growth factor-I axis and cytokine levels, such as leptin, IL-1β, TGF-β and tumor necrosis factor (TNF)-α (75). This fetoplacental unit disruption, caused by maternal PCB exposure, might reduce normal biological function and the general health of the offspring.

6. Conclusions

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.

Availability of data and materials

Not applicable.

Authors' contributions

YFW wrote the manuscript. CCH investigated the association between gestational PCBs exposure and progeny nervous system development. TF contributed to the mechanisms of PCBs. YJ contributed to analysis of epidemiological differences. RJW supervised and revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

References

1 

Klocke C, Sethi S and Lein PJ: The developmental neurotoxicity of legacy vs. contemporary polychlorinated biphenyls (PCBs): Similarities and differences. Environ Sci Pollut Res Int. 27:8885–8896. 2020. View Article : Google Scholar :

2 

Garmash O, Hermanson MH, Isaksson E, Schwikowski M, Divine D, Teixeira C and Muir DC: Deposition history of polychlorinated biphenyls to the Lomonosovfonna Glacier, Svalbard: A 209 congener analysis. Environ Sci Technol. 47:12064–12072. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Steinberg RM, Walker DM, Juenger TE, Woller MJ and Gore AC: Effects of perinatal polychlorinated biphenyls on adult female rat reproduction: Development, reproductive physiology, and second generational effects. Biol Reprod. 78:1091–1101. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Malisch R and Kotz A: Dioxins and PCBs in feed and food-review from European perspective. Sci Total Environ. 491-492:2–10. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Adams EM, von Hippel FA, Hungate BA and Buck CL: Polychlorinated biphenyl (PCB) contamination of subsistence species on Unalaska Island in the Aleutian Archipelago. Heliyon. 5:e029892019. View Article : Google Scholar :

6 

Sharma JK, Gautam RK, Misra RR, Kashyap SM, Singh SK and Juwarkar AA: Degradation of Di-Through Hepta-Chlorobiphenyls in clophen oil using microorganisms isolated from long term PCBs contaminated soil. Indian J Microbiol. 54:337–342. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Kohler M, Tremp J, Zennegg M, Seiler C, Minder-Kohler S, Beck M, Lienemann P, Wegmann L and Schmid P: Joint sealants: An overlooked diffuse source of polychlorinated biphenyls in buildings. Environ Sci Technol. 39:1967–1973. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Han W, Feng J, Gu Z, Wu M, Sheng G and Fu J: Polychlorinated biphenyls in the atmosphere of Taizhou, a major e-waste dismantling area in China. J Environ Sci (China). 22:589–597. 2010. View Article : Google Scholar

9 

Arp HPH, Morin NAO, Andersson PL, Hale SE, Wania F, Breivik K and Breedveld GD: The presence, emission and partitioning behavior of polychlorinated biphenyls in waste, leachate and aerosols from Norwegian waste-handling facilities. Sci Total Environ. 715:1368242020. View Article : Google Scholar : PubMed/NCBI

10 

Chang CJ, Terrell ML, Marcus M, Marder ME, Panuwet P, Ryan PB, Pearson M, Barton H and Barr DB: Serum concentrations of polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the Michigan PBB Registry 40 years after the PBB contamination incident. Environ Int. 137:1055262020. View Article : Google Scholar :

11 

Hales CN and Barker DJ: Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia. 35:595–601. 1992. View Article : Google Scholar : PubMed/NCBI

12 

Magalhães ESDS, Méio MDBB and Moreira MEL: Hormonal biomarkers for evaluating the impact of fetal growth restriction on the development of chronic adult disease. Rev Bras Ginecol Obstet. 41:256–263. 2019. View Article : Google Scholar : PubMed/NCBI

13 

Preston JD, Reynolds LJ and Pearson KJ: Developmental origins of health span and life span: A mini-review. Gerontology. 64:237–245. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Rice D and Barone S Jr: Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environ Health Perspect. 108(Suppl 3): S511–S533. 2000.

15 

Chu CP, Wu SW, Huang YJ, Chiang MC, Hsieh ST and Guo YL: Neuroimaging signatures of brain plasticity in adults with prenatal exposure to polychlorinated biphenyls: Altered functional connectivity on functional MRI. Environ Pollut. 250:960–968. 2019. View Article : Google Scholar : PubMed/NCBI

16 

Perera F and Herbstman J: Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol. 31:363–373. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Zhu Z, Cao F and Li X: Epigenetic programming and fetal metabolic programming. Front Endocrinol (Lausanne). 10:7642019. View Article : Google Scholar

18 

Casati L, Sendra R, Colciago A, Negri-Cesi P, Berdasco M, Esteller M and Celotti F: Polychlorinated biphenyls affect histone modification pattern in early development of rats: A role for androgen receptor-dependent modulation? Epigenomics. 4:101–112. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Vermeir G, Covaci A, Van Larebeke N, Schoeters G, Nelen V, Koppen G and Viaene M: Neurobehavioural and cognitive effects of prenatal exposure to organochlorine compounds in three year old children. BMC Pediatr. 21:992021. View Article : Google Scholar : PubMed/NCBI

20 

Zhang H, Yolton K, Webster GM, Sjödin A, Calafat AM, Dietrich KN, Xu Y, Xie C, Braun JM, Lanphear BP and Chen A: Prenatal PBDE and PCB exposures and reading, cognition, and externalizing behavior in children. Environ Health Perspect. 125:746–752. 2017. View Article : Google Scholar :

21 

Berghuis SA, Van Braeckel KNJA, Sauer PJJ and Bos AF: Prenatal exposure to persistent organic pollutants and cognition and motor performance in adolescence. Environ Int. 121(Pt 1): 13–22. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Longnecker MP, Hoffman HJ, Klebanoff MA, Brock JW, Zhou H, Needham L, Adera T, Guo X and Gray KA: In utero exposure to polychlorinated biphenyls and sensorineural hearing loss in 8-year-old children. Neurotoxicol Teratol. 26:629–637. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Granillo L, Sethi S, Keil KP, Lin Y, Ozonoff S, Iosif AM, Puschner B and Schmidt RJ: Polychlorinated biphenyls influence on autism spectrum disorder risk in the MARBLES cohort. Environ Res. 171:177–184. 2019. View Article : Google Scholar : PubMed/NCBI

24 

Macdonal RW, Barrie LA, Bidleman TF, Diamond ML, Gregor DJ, Semkin RG, Strachan WM, Li YF, Wania F, Alaee M, et al: Contaminants in the Canadian arctic: 5 years of progress in understanding sources, occurrence and pathways. Sci Total Environ. 254:93–234. 2000. View Article : Google Scholar : PubMed/NCBI

25 

Desforges JP, Hall A, McConnell B, Rosing-Asvid A, Barber JL, Brownlow A, De Guise S, Eulaers I, Jepson PD, Letcher RJ, et al: Predicting global killer whale population collapse from PCB pollution. Science. 361:1373–1376. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Lohmann R, Gioia R, Jones KC, Nizzetto L, Temme C, Xie Z, Schulz-Bull D, Hand I, Morgan E and Jantunen L: Organochlorine pesticides and PAHs in the surface water and atmosphere of the North Atlantic and Arctic Ocean. Environ Sci Technol. 43:5633–5639. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Te B, Yiming L, Tianwei L, Huiting W, Pengyuan Z, Wenming C and Jun J: Polychlorinated biphenyls in a grassland food network: Concentrations, biomagnification, and transmission of toxicity. Sci Total Environ. 709:1357812020. View Article : Google Scholar

28 

Pajewska-Szmyt M, Sinkiewicz-Darol E and Gadzala-Kopciuch R: The impact of environmental pollution on the quality of mother's milk. Environ Sci Pollut Res Int. 26:7405–7427. 2019. View Article : Google Scholar : PubMed/NCBI

29 

Portoles T, Sales C, Abalos M, Saulo J and Abad E: Evaluation of the capabilities of atmospheric pressure chemical ionization source coupled to tandem mass spectrometry for the determination of dioxin-like polychlorobiphenyls in complex-matrix food samples. Anal Chim Acta. 937:96–105. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Son MH, Kim JT, Park H, Kim M, Paek OJ and Chang YS: Assessment of the daily intake of 62 polychlorinated biphenyls from dietary exposure in South Korea. Chemosphere. 89:957–963. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Ebadi Fathabad A, Tajik H, Jafari K, Hoseinzadeh E, Mirahmadi SS, Conti GO and Miri M: Evaluation of dioxin-like polychlorinated biphenyls in fish of the Caspian Sea. MethodsX. 7:1008032020. View Article : Google Scholar : PubMed/NCBI

32 

Borrell LN, Factor-Litvak P, Wolff MS, Susser E and Matte TD: Effect of socioeconomic status on exposures to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) among pregnant African-American women. Arch Environ Health. 59:250–255. 2004. View Article : Google Scholar

33 

Takagi Y, Aburada S, Hashimoto K and Kitaura T: Transfer and distribution of accumulated (14C)polychlorinated biphenyls from maternal to fetal and suckling rats. Arch Environ Contam Toxicol. 15:709–715. 1986. View Article : Google Scholar : PubMed/NCBI

34 

Uemura H, Arisawa K, Hiyoshi M, Satoh H, Sumiyoshi Y, Morinaga K, Kodama K and Suzuki T, Nagai M and Suzuki T: PCDDs/PCDFs and dioxin-like PCBs: Recent body burden levels and their determinants among general inhabitants in Japan. Chemosphere. 73:30–37. 2008. View Article : Google Scholar : PubMed/NCBI

35 

Ulaszewska MM, Zuccato E and Davoli E: PCDD/Fs and dioxin-like PCBs in human milk and estimation of infants' daily intake: A review. Chemosphere. 83:774–782. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Simic I, Jovanovic G, Herceg Romanic S, Klincic D, Matek Saric M and Popovic A: Optimization of Gas Chromatography-electron Ionization-tandem mass spectrometry for determining Toxic Non-ortho polychlorinated biphenyls in breast milk. Biomed Environ Sci. 33:58–61. 2020.

37 

Cok I, Donmez MK, Uner M, Demirkaya E, Henkelmann B, Shen H, Kotalik J and Schramm KW: Polychlorinated dibenzo-p-dioxins, dibenzofurans and polychlorinated biphenyls levels in human breast milk from different regions of Turkey. Chemosphere. 76:1563–1571. 2009. View Article : Google Scholar : PubMed/NCBI

38 

Miniscalco C, Nygren G, Hagberg B, Kadesjo B and Gillberg C: Neuropsychiatric and neurodevelopmental outcome of children at age 6 and 7 years who screened positive for language problems at 30 months. Dev Med Child Neurol. 48:361–366. 2006. View Article : Google Scholar : PubMed/NCBI

39 

Clegg J, Hollis C, Mawhood L and Rutter M: Developmental language disorders-a follow-up in later adult life. Cognitive, language and psychosocial outcomes. J Child Psychol Psychiatry. 46:128–149. 2005. View Article : Google Scholar : PubMed/NCBI

40 

Caspersen IH, Haugen M, Schjølberg S, Vejrup K, Knutsen HK, Brantsæter AL, Meltzer HM, Alexander J, Magnus P and Kvalem HE: Maternal dietary exposure to dioxins and polychlorinated biphenyls (PCBs) is associated with language delay in 3year old Norwegian children. Environ Int. 91:180–187. 2016. View Article : Google Scholar : PubMed/NCBI

41 

Grandjean P, Weihe P, Nielsen F, Heinzow B, Debes F and Budtz-Jorgensen E: Neurobehavioral deficits at age 7 years associated with prenatal exposure to toxicants from maternal seafood diet. Neurotoxicol Teratol. 34:466–472. 2012. View Article : Google Scholar : PubMed/NCBI

42 

Berghuis SA, Soechitram SD, Sauer PJ and Bos AF: Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with neurological functioning in 3-month-old infants. Toxicol Sci. 142:455–462. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Gladen BC and Rogan WJ: Effects of perinatal polychlorinated biphenyls and dichlorodiphenyl dichloroethene on later development. J Pediatr. 119(1 Pt 1): 58–63. 1991. View Article : Google Scholar : PubMed/NCBI

44 

Jacobson JL and Jacobson SW: Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 335:783–789. 1996. View Article : Google Scholar : PubMed/NCBI

45 

Newman J, Gallo MV, Schell LM, DeCaprio AP, Denham M and Deane GD; Akwesasne Task Force on Environment: Analysis of PCB congeners related to cognitive functioning in adolescents. Neurotoxicology. 30:686–696. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Grandjean P, Weihe P, Burse VW, Needham LL, Storr-Hansen E, Heinzow B, Debes F, Murata K, Simonsen H, Ellefsen P, et al: Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants. Neurotoxicol Teratol. 23:305–317. 2001. View Article : Google Scholar : PubMed/NCBI

47 

Jusko TA, Sisto R, Iosif AM, Moleti A, Wimmerová S, Lancz K, Tihányi J, Sovčiková E, Drobná B, Palkovičová L, et al: Prenatal and postnatal serum PCB concentrations and cochlear function in children at 45 months of age. Environ Health Perspect. 122:1246–1252. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Perry KJ and Price JM: Concurrent child history and contextual predictors of children's internalizing and externalizing behavior problems in foster care. Child Youth Serv Rev. 84:125–136. 2018. View Article : Google Scholar : PubMed/NCBI

49 

Tatsuta N, Nakai K, Murata K, Suzuki K, Iwai-Shimada M, Yaginuma-Sakurai K, Kurokawa N, Nakamura T, Hosokawa T and Satoh H: Prenatal exposures to environmental chemicals and birth order as risk factors for child behavior problems. Environ Res. 114:47–52. 2012. View Article : Google Scholar : PubMed/NCBI

50 

Gonzalez ST, Remick D, Creton R and Colwill RM: Effects of embryonic exposure to polychlorinated biphenyls (PCBs) on anxiety-related behaviors in larval zebrafish. Neurotoxicology. 53:93–101. 2016. View Article : Google Scholar : PubMed/NCBI

51 

Lovato AK, Creton R and Colwill RM: Effects of embryonic exposure to polychlorinated biphenyls (PCBs) on larval zebrafish behavior. Neurotoxicol Teratol. 53:1–10. 2016. View Article : Google Scholar

52 

Glazer L, Hahn ME and Aluru N: Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior. Neurotoxicology. 52:134–143. 2016. View Article : Google Scholar

53 

Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M and Windham GC: Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal mid-pregnancy serum samples: Association with autism spectrum disorder and intellectual disability. Environ Health Perspect. 125:474–480. 2017. View Article : Google Scholar :

54 

Bernardo BA, Lanphear BP, Venners SA, Arbuckle TE, Braun JM, Muckle G, Fraser WD and McCandless LC: Assessing the relation between plasma PCB concentrations and elevated autistic behaviours using bayesian predictive odds ratios. Int J Environ Res Public Health. 16:4572019. View Article : Google Scholar :

55 

Teodoro M, Briguglio G, Fenga C and Costa C: Genetic polymorphisms as determinants of pesticide toxicity: Recent advances. Toxicol Rep. 6:564–570. 2019. View Article : Google Scholar : PubMed/NCBI

56 

Costa C, Briguglio G, Giambò F, Catanoso R, Teodoro M, Caccamo D and Fenga C: Association between oxidative stress biomarkers and PON and GST polymorphisms as a predictor for susceptibility to the effects of pesticides. Int J Mol Med. 45:1951–1959. 2020.PubMed/NCBI

57 

Costa C, Gangemi S, Giambo F, Rapisarda V, Caccamo D and Fenga C: Oxidative stress biomarkers and paraoxonase 1 polymorphism frequency in farmers occupationally exposed to pesticides. Mol Med Rep. 12:6353–6357. 2015. View Article : Google Scholar : PubMed/NCBI

58 

Colter BT, Garber HF, Fleming SM, Fowler JP, Harding GD, Hooven MK, Howes AA, Infante SK, Lang AL, MacDougall MC, et al: Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls. Neurotoxicology. 65:125–134. 2018. View Article : Google Scholar : PubMed/NCBI

59 

Docea AO, Vassilopoulou L, Fragou D, Arsene AL, Fenga C, Kovatsi L, Petrakis D, Rakitskii VN, Nosyrev AE, Izotov BN, et al: CYP polymorphisms and pathological conditions related to chronic exposure to organochlorine pesticides. Toxicol Rep. 4:335–341. 2017. View Article : Google Scholar : PubMed/NCBI

60 

Curran CP, Nebert DW, Genter MB, Patel KV, Schaefer TL, Skelton MR, Williams MT and Vorhees CV: In utero and lactational exposure to PCBs in mice: Adult offspring show altered learning and memory depending on Cyp1a2 and Ahr genotypes. Environ Health Perspect. 119:1286–1293. 2011. View Article : Google Scholar : PubMed/NCBI

61 

Hufgard JR, Sprowles JLN, Pitzer EM, Koch SE, Jiang M, Wang Q, Zhang X, Biesiada J, Rubinstein J, Puga A, et al: Prenatal exposure to PCBs in Cyp1a2 knock-out mice interferes with F1 fertility, impairs long-term potentiation, reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects. J Appl Toxicol. 39:603–621. 2019. View Article : Google Scholar

62 

Klinefelter K, Hooven MK, Bates C, Colter BT, Dailey A, Infante SK, Kania-Korwel I, Lehmler HJ, López-Juárez A, Ludwig CP and Curran CP: Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders. Mamm Genome. 29:112–127. 2018. View Article : Google Scholar

63 

Nebert DW and Dalton TP: The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 6:947–960. 2006. View Article : Google Scholar : PubMed/NCBI

64 

Rude KM, Pusceddu MM, Keogh CE, Sladek JA, Rabasa G, Miller EN, Sethi S, Keil KP, Pessah IN, Lein PJ and Gareau MG: Developmental exposure to polychlorinated biphenyls (PCBs) in the maternal diet causes host-microbe defects in weanling offspring mice. Environ Pollut. 253:708–721. 2019. View Article : Google Scholar : PubMed/NCBI

65 

Sanctuary MR, Kain JN, Angkustsiri K and German JB: Dietary considerations in autism spectrum disorders: The potential role of protein digestion and microbial putrefaction in the gut-brain axis. Front Nutr. 5:402018. View Article : Google Scholar : PubMed/NCBI

66 

Dai R, Yu Y, Xi Q, Hu X, Zhu H, Liu R and Wang R: Prenatal diagnosis of 4953 pregnant women with indications for genetic amniocentesis in Northeast China. Mol Cytogenet. 12:452019. View Article : Google Scholar : PubMed/NCBI

67 

Long M, Ghisari M, Kjeldsen L, Wielsøe M, Nørgaard-Pedersen B, Mortensen EL, Abdallah MW and Bonefeld-Jørgensen EC: Autism spectrum disorders, endocrine disrupting compounds, and heavy metals in amniotic fluid: A case-control study. Mol Autism. 10:12019. View Article : Google Scholar : PubMed/NCBI

68 

Berghuis SA, Soechitram SD, Hitzert MM, Sauer PJ and Bos AF: Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with motor development of three-month-old infants. Neurotoxicology. 38:124–130. 2013. View Article : Google Scholar : PubMed/NCBI

69 

Tatsuta N, Kurokawa N, Nakai K, Suzuki K, Iwai-Shimada M, Murata K and Satoh H: Effects of intrauterine exposures to polychlorinated biphenyls, methylmercury, and lead on birth weight in Japanese male and female newborns. Environ Health Prev Med. 22:392017. View Article : Google Scholar : PubMed/NCBI

70 

Sonneborn D, Park HY, Petrik J, Kocan A, Palkovicova L, Trnovec T, Nguyen D and Hertz-Picciotto I: Prenatal polychlorinated biphenyl exposures in eastern Slovakia modify effects of social factors on birthweight. Paediatr Perinat Epidemiol. 22:202–213. 2008. View Article : Google Scholar : PubMed/NCBI

71 

Calo M, Licata P, Bitto A, Lo Cascio P, Interdonato M and Altavilla D: Role of AHR, AHRR and ARNT in response to dioxin-like PCBs in Spaurus aurata. Environ Sci Pollut Res Int. 21:14226–14231. 2014. View Article : Google Scholar : PubMed/NCBI

72 

Pessah IN, Cherednichenko G and Lein PJ: Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther. 125:260–285. 2010. View Article : Google Scholar :

73 

Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, Greenough WT, Pessah IN and Schantz SL: Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicol Teratol. 28:74–85. 2006. View Article : Google Scholar

74 

Kalkunte S, Huang Z, Lippe E, Kumar S, Robertson LW and Sharma S: Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects. Sci Rep. 7:398852017. View Article : Google Scholar : PubMed/NCBI

75 

Ahmed RG, El-Gareib AW and Shaker HM: Gestational 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure disrupts fetoplacental unit: Fetal thyroid-cytokines dysfunction. Life Sci. 192:213–220. 2018. View Article : Google Scholar

76 

Aluru N, Karchner SI and Glazer L: Early life exposure to low levels of AHR Agonist PCB126 (3,3′,4,4′,5-Pentachlorobiphenyl) reprograms gene expression in adult brain. Toxicol Sci. 160:386–397. 2017. View Article : Google Scholar : PubMed/NCBI

77 

Kappil MA, Li Q, Li A, Dassanayake PS, Xia Y, Nanes JA, Landrigan PJ, Stodgell CJ, Aagaard KM, Schadt EE, et al: In utero exposures to environmental organic pollutants disrupt epigenetic marks linked to fetoplacental development. Environ Epigenet. 2:dvv0132016. View Article : Google Scholar :

78 

Seegal RF, Brosch KO and Okoniewski RJ: Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: Implications for developmental neurotoxicity. Toxicol Sci. 86:125–131. 2005. View Article : Google Scholar : PubMed/NCBI

79 

Pappas B, Yang Y, Wang Y, Kim K, Chung HJ, Cheung M, Ngo K, Shinn A and Chan WK: p23 protects the human aryl hydrocarbon receptor from degradation via a heat shock protein 90-independent mechanism. Biochem Pharmacol. 152:34–44. 2018. View Article : Google Scholar : PubMed/NCBI

80 

Jain S, Maltepe E, Lu MM, Simon C and Bradfield CA: Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev. 73:117–123. 1998. View Article : Google Scholar : PubMed/NCBI

81 

Kimura E and Tohyama C: Embryonic and postnatal expression of aryl hydrocarbon receptor mRNA in mouse brain. Front Neuroanat. 11:42017. View Article : Google Scholar : PubMed/NCBI

82 

Shi H, Hardesty JE, Jin J, Head KZ, Falkner KC, Cave MC and Prough RA: Concentration dependence of human and mouse aryl hydrocarbon receptor responsiveness to polychlorinated biphenyl exposures: Implications for aroclor mixtures. Xenobiotica. 49:1414–1422. 2019. View Article : Google Scholar : PubMed/NCBI

83 

Juricek L and Coumoul X: The aryl hydrocarbon receptor and the nervous system. Int J Mol Sci. 19:25042018. View Article : Google Scholar :

84 

Chatonnet F, Boudinot E, Chatonnet A, Taysse L, Daulon S, Champagnat J and Foutz AS: Respiratory survival mechanisms in acetylcholinesterase knockout mouse. Eur J Neurosci. 18:1419–1427. 2003. View Article : Google Scholar : PubMed/NCBI

85 

Desaulniers D, Xiao GH, Leingartner K, Chu I, Musicki B and Tsang BK: Comparisons of brain, uterus, and liver mRNA expression for cytochrome p450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists. Toxicol Sci. 86:175–184. 2005. View Article : Google Scholar : PubMed/NCBI

86 

Kimura E, Kubo KI, Endo T, Nakajima K, Kakeyama M and Tohyama C: Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse. J Toxicol Sci. 42:25–30. 2017. View Article : Google Scholar : PubMed/NCBI

87 

Fritsch EB, Stegeman JJ, Goldstone JV, Nacci DE, Champlin D, Jayaraman S, Connon RE and Pessah IN: Expression and function of ryanodine receptor related pathways in PCB tolerant Atlantic killifish (Fundulus heteroclitus) from New Bedford Harbor, MA, USA. Aquat Toxicol. 159:156–166. 2015. View Article : Google Scholar :

88 

Sethi S, Morgan RK, Feng W, Lin Y, Li X, Luna C, Koch M, Bansal R, Duffel MW, Puschner B, et al: Comparative analyses of the 12 most abundant PCB congeners detected in human maternal serum for activity at the thyroid hormone receptor and ryanodine receptor. Environ Sci Technol. 53:3948–3958. 2019. View Article : Google Scholar : PubMed/NCBI

89 

Libersat F and Duch C: Mechanisms of dendritic maturation. Mol Neurobiol. 29:303–320. 2004. View Article : Google Scholar : PubMed/NCBI

90 

Pittenger C and Kandel ER: In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Philos Trans R Soc Lond B Biol Sci. 358:757–763. 2003. View Article : Google Scholar : PubMed/NCBI

91 

Wayman GA, Yang D, Bose DD, Lesiak A, Ledoux V, Bruun D, Pessah IN and Lein PJ: PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environ Health Perspect. 120:997–1002. 2012. View Article : Google Scholar : PubMed/NCBI

92 

Yang D, Kania-Korwel I, Ghogha A, Chen H, Stamou M, Bose DD, Pessah IN, Lehmler HJ and Lein PJ: PCB 136 atropselectively alters morphometric and functional parameters of neuronal connectivity in cultured rat hippocampal neurons via ryanodine receptor-dependent mechanisms. Toxicol Sci. 138:379–392. 2014. View Article : Google Scholar : PubMed/NCBI

93 

Feng W, Zheng J, Robin G, Dong Y, Ichikawa M, Inoue Y, Mori T, Nakano T and Pessah IN: Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) atropisomers toward ryanodine receptors (RyRs) and their influences on hippocampal neuronal networks. Environ Sci Technol. 51:14406–14416. 2017. View Article : Google Scholar : PubMed/NCBI

94 

Wayman GA, Bose DD, Yang D, Lesiak A, Bruun D, Impey S, Ledoux V, Pessah IN and Lein PJ: PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environ Health Perspect. 120:1003–1009. 2012. View Article : Google Scholar : PubMed/NCBI

95 

Howard AS, Fitzpatrick R, Pessah I, Kostyniak P and Lein PJ: Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicol Appl Pharmacol. 190:72–86. 2003. View Article : Google Scholar : PubMed/NCBI

96 

Sethi S, Keil KP, Chen H, Hayakawa K, Li X, Lin Y, Lehmler HJ, Puschner B and Lein PJ: Detection of 3,3′-Dichlorobiphenyl in human maternal plasma and its effects on axonal and dendritic growth in primary rat neurons. Toxicol Sci. 158:401–411. 2017. View Article : Google Scholar : PubMed/NCBI

97 

Casati L, Sendra R, Poletti A, Negri-Cesi P and Celotti F: Androgen receptor activation by polychlorinated biphenyls: Epigenetic effects mediated by the histone demethylase Jarid1b. Epigenetics. 8:1061–1068. 2013. View Article : Google Scholar : PubMed/NCBI

98 

Kanherkar RR, Bhatia-Dey N and Csoka AB: Epigenetics across the human lifespan. Front Cell Dev Biol. 2:492014. View Article : Google Scholar : PubMed/NCBI

99 

Su KY, Li MC, Lee NW, Ho BC, Cheng CL, Chuang YC, Yu SL and Guo YL: Perinatal polychlorinated biphenyls and polychlorinated dibenzofurans exposure are associated with DNA methylation changes lasting to early adulthood: Findings from Yucheng second generation. Environ Res. 170:481–486. 2019. View Article : Google Scholar : PubMed/NCBI

100 

Leung YK, Ouyang B, Niu L, Xie C, Ying J, Medvedovic M, Chen A, Weihe P, Valvi D, Grandjean P and Ho SM: Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort. Epigenetics. 13:290–300. 2018. View Article : Google Scholar : PubMed/NCBI

101 

Guo F, Yan L, Guo H, Li L, Hu B, Zhao Y, Yong J, Hu Y, Wang X, Wei Y, et al: The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell. 161:1437–1452. 2015. View Article : Google Scholar : PubMed/NCBI

102 

Pozharny Y, Lambertini L, Ma Y, Ferrara L, Litton CG, Diplas A, Jacobs AR, Chen J, Stone JL, Wetmur J and Lee MJ: Genomic loss of imprinting in first-trimester human placenta. Am J Obstet Gynecol. 202:391.e1–e8. 2010. View Article : Google Scholar

103 

Zhao Y, Song Q, Ge W, Jin Y, Chen S, Zhao Y, Xiao X and Zhang Y: Associations between in utero exposure to polybrominated diphenyl ethers, pathophysiological state of fetal growth and placental DNA methylation changes. Environ Int. 133(Pt B): 1052552019. View Article : Google Scholar : PubMed/NCBI

104 

Maghbooli Z, Hossein-Nezhad A, Adabi E, Asadollah-Pour E, Sadeghi M, Mohammad-Nabi S, Zakeri Rad L, Malek Hosseini AA, Radmehr M, Faghihi F, et al: Air pollution during pregnancy and placental adaptation in the levels of global DNA methylation. PLoS One. 13:e01997722018. View Article : Google Scholar : PubMed/NCBI

105 

Dunaway KW, Islam MS, Coulson RL, Lopez SJ, Vogel Ciernia A, Chu RG, Yasui DH, Pessah IN, Lott P, Mordaunt C, et al: Cumulative impact of polychlorinated biphenyl and large chromosomal duplications on DNA methylation, chromatin, and expression of autism candidate genes. Cell Rep. 17:3035–3048. 2016. View Article : Google Scholar : PubMed/NCBI

106 

Wefers B, Hitz C, Hölter SM, Trümbach D, Hansen J, Weber P, Pütz B, Deussing JM, de Angelis MH, Roenneberg T, et al: MAPK signaling determines anxiety in the juvenile mouse brain but depression-like behavior in adults. PLoS One. 7:e350352012. View Article : Google Scholar : PubMed/NCBI

107 

Naveau E, Pinson A, Gérard A, Nguyen L, Charlier C, Thomé JP, Zoeller RT, Bourguignon JP and Parent AS: Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls. PLoS One. 9:e919032014. View Article : Google Scholar : PubMed/NCBI

108 

Seegal RF: Epidemiological and laboratory evidence of PCB-induced neurotoxicity. Crit Rev Toxicol. 26:709–737. 1996. View Article : Google Scholar : PubMed/NCBI

109 

Caspersen IH, Aase H, Biele G, Brantsæter AL, Haugen M, Kvalem HE, Skogan AH, Zeiner P, Alexander J, Meltzer HM and Knutsen HK: The influence of maternal dietary exposure to dioxins and PCBs during pregnancy on ADHD symptoms and cognitive functions in Norwegian preschool children. Environ Int. 94:649–660. 2016. View Article : Google Scholar : PubMed/NCBI

110 

Morreale de Escobar G, Obregon MJ and Escobar del Rey F: Role of thyroid hormone during early brain development. Eur J Endocrinol. 151(Suppl 3): U25–U37. 2004. View Article : Google Scholar : PubMed/NCBI

111 

Gilbert ME, O'Shaughnessy KL and Axelstad M: Regulation of thyroid-disrupting chemicals to protect the developing brain. Endocrinology. 161:bqaa1062020. View Article : Google Scholar : PubMed/NCBI

112 

Levitt P, Eagleson KL and Powell EM: Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci. 27:400–406. 2004. View Article : Google Scholar : PubMed/NCBI

113 

Chan SY, Vasilopoulou E and Kilby MD: The role of the placenta in thyroid hormone delivery to the fetus. Nat Clin Pract Endocrinol Metab. 5:45–54. 2009. View Article : Google Scholar

114 

Li ZM, Hernandez-Moreno D, Main KM, Skakkebæk NE, Kiviranta H, Toppari J, Feldt-Rasmussen U, Shen H, Schramm KW and De Angelis M: Association of in utero persistent organic pollutant exposure with placental thyroid hormones. Endocrinology. 159:3473–3481. 2018. View Article : Google Scholar : PubMed/NCBI

115 

Itoh S, Baba T, Yuasa M, Miyashita C, Kobayashi S, Araki A, Sasaki S, Kajiwara J, Hori T, Todaka T, et al: Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study. Environ Res. 167:583–590. 2018. View Article : Google Scholar : PubMed/NCBI

116 

Su PH, Chen HY, Chen SJ, Chen JY, Liou SH and Wang SL: Thyroid and growth hormone concentrations in 8-year-old children exposed in utero to dioxins and polychlorinated biphenyls. J Toxicol Sci. 40:309–319. 2015. View Article : Google Scholar : PubMed/NCBI

117 

Boas M, Feldt-Rasmussen U and Main KM: Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol. 355:240–248. 2012. View Article : Google Scholar

118 

Lyng GD, Snyder-Keller A and Seegal RF: Polychlorinated biphenyl-induced neurotoxicity in organotypic cocultures of developing rat ventral mesencephalon and striatum. Toxicol Sci. 97:128–139. 2007. View Article : Google Scholar : PubMed/NCBI

119 

Kalkunte SS, Mselle TF, Norris WE, Wira CR, Sentman CL and Sharma S: Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface. J Immunol. 182:4085–4092. 2009. View Article : Google Scholar : PubMed/NCBI

120 

Osol G, Ko NL and Mandala M: Plasticity of the maternal vasculature during pregnancy. Annu Rev Physiol. 81:89–111. 2019. View Article : Google Scholar : PubMed/NCBI

121 

Chen ZJ, Liu HY, Cheng Z, Man YB, Zhang KS, Wei W, Du J, Wong MH and Wang HS: Polybrominated diphenyl ethers (PBDEs) in human samples of mother-newborn pairs in South China and their placental transfer characteristics. Environ Int. 73:77–84. 2014. View Article : Google Scholar : PubMed/NCBI

122 

Brucker-Davis F, Ferrari P, Boda-Buccino M, Wagner-Mahler K, Pacini P, Gal J, Azuar P and Fenichel P: Cord blood thyroid tests in boys born with and without cryptorchidism: Correlations with birth parameters and in utero xenobiotics exposure. Thyroid. 21:1133–1141. 2011. View Article : Google Scholar : PubMed/NCBI

123 

Hellstrom M, Phng LK and Gerhardt H: VEGF and Notch signaling: The yin and yang of angiogenic sprouting. Cell Adh Migr. 1:133–136. 2007. View Article : Google Scholar : PubMed/NCBI

124 

Hunkapiller NM, Gasperowicz M, Kapidzic M, Plaks V, Maltepe E, Kitajewski J, Cross JC and Fisher SJ: A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development. 138:2987–2998. 2011. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August-2021
Volume 48 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang Y, Hu C, Fang T, Jin Y and Wu R: Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review). Int J Mol Med 48: 150, 2021
APA
Wang, Y., Hu, C., Fang, T., Jin, Y., & Wu, R. (2021). Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review). International Journal of Molecular Medicine, 48, 150. https://doi.org/10.3892/ijmm.2021.4983
MLA
Wang, Y., Hu, C., Fang, T., Jin, Y., Wu, R."Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)". International Journal of Molecular Medicine 48.2 (2021): 150.
Chicago
Wang, Y., Hu, C., Fang, T., Jin, Y., Wu, R."Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review)". International Journal of Molecular Medicine 48, no. 2 (2021): 150. https://doi.org/10.3892/ijmm.2021.4983