Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity
Abstract
:1. Introduction
2. PCB Nomenclature and Classifications
3. Neurobehavioral Studies of PCB Developmental Neurotoxicity
3.1. Hyperactivity
3.2. Social Deficits
3.3. Cognitive Impairment and Executive Dysfunction
4. Neurodevelopmental Processes Altered by PCBs
4.1. PCB Effects on Neuronal Apoptosis
4.2. PCB Effects on Axonal and Dendritic Morphogenesis
5. Molecular Mechanisms of PCB Developmental Neurotoxicity
5.1. Arylhydrocarbon Receptor (AhR) as a Molecular Target in PCB Developmental Neurotoxicity
5.2. Thyroid Hormone-Mediated Mechanisms of PCB Developmental Neurotoxicity
5.3. Calcium Signaling
5.4. Increased ROS as a Mechanism of PCB Developmental Neurotoxicity
6. Emerging Evidence that Non-Legacy LC-PCBs Interfere with Typical Neurodevelopment
7. Relevance of PCB Developmental Neurotoxicity to NDDs
8. Conclusions, Data Gaps, and Directions for Future Study
Funding
Conflicts of Interest
Abbreviations
ABR | Auditory brain stem response |
ADHD | Attention-deficit hyperactivity disorder |
AhR | Arylhydrocarbon receptor |
ASD | Autism spectrum disorder |
bHLH/PAS | Basic helix-loop-helix/Per-Arnt-Sim |
CREB | cAMP response element-binding protein |
DL | Dioxin-like |
DNT | Developmental neurotoxicity |
DRL | Differential reinforcement of low-rate |
DSA | Delayed spatial alternation |
EPM | Elevated plus maze |
GD | Gestational day |
4-HNE | 4-Hydroxynonenal |
GWAS | Genome-wide association study |
LDB | Light-dark box |
MWM | Morris water maze |
NDD | Neurodevelopmental disorder |
NDL | Non-dioxin-like |
NOR | Novel object recognition |
3-NT | 3-Nitrotyrosine |
PCB | Polychlorinated biphenyl |
PKC | Protein kinase C |
PND | Postnatal day |
POPs | Persistent organic pollutants |
ROS | Reactive oxygen species |
RyR | Ryanodine receptor |
SAR | Structure activity relationship |
SNP | Single nucleotide polymorphism |
T4 | Thyroxine |
TCDD | 2,3,7,8-Tetrachlorodibenzo-p-dioxin |
TH | Thyroid hormone |
THR | Thyroid hormone receptor |
TUNEL | Terminal deoxynucelotidyl transferase nick-end labeling |
U.S. | United States |
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Model | Exposure | Dose(s) | Route of Exposure | Exposure Window | Findings | Ref. |
---|---|---|---|---|---|---|
Mouse (ICR) | A1254 | 6 mg/kg/d, 18 mg/kg/d | Gavage | Lactation (PND 7–21), Postnatal (PND 22–42) | ↑ Locomotor activity in females | [74] |
Mouse (ICR) | A1254 | 18 mg/kg/d | Injection (i.p.) | Prenatal (GD 6-PND 0), Lactation (PND 0–21) | ↑ Locomotor activity | [75] |
Mouse (Swiss albino) | NDL PCB mixture (PCBs 28, 52, 101, 138, 153, 180) | 1 ng/kg/d, 10 ng/kg/d, 100 ng/kg/d | Gavage | Lactation (PND 0–21) | ↓ Locomotor activity in 1 and 10 ng/kg males | [76] |
Rat (Sprague-Dawley) | A1221 | 0.5 mg/kg, 1 mg/kg | Injection (i.p.) | Prenatal (GD 16, 18) | ↑ Distance traveled in LDB in male offspring | [77] |
Rat (Wistar) | PCB 52, PCB 138, PCB 180 | 1 mg/kg/d | Dietary (jelly) | Prenatal (GD 7-PND 0), Lactation (PND 0–21) | ↓ Locomotor activity in PCB 138 and PCB 180 groups in males; ↓ Locomotor activity in PCB 138 group in females | [78] |
Rat (Wistar) | PCB 52, PCB 138, PCB 180 | 1 mg/kg/d | Dietary (jelly) | Prenatal (GD 7-PND 0), Lactation (PND 0–21) | ↓ Time spent on rotarod in PCB 52 group for both sexes | [79] |
Model | Exposure | Dose(s) | Route of Exposure | Exposure Window | Findings | Ref. |
---|---|---|---|---|---|---|
Mouse (CD1) | NDL PCB mixture (PCBs 28, 52, 101, 138, 153, 180) | 10 ng/kg/d, 1 µg/kg/d | Dietary (chow) | Prenatal (GD 6-PND 0), Lactation (PND 0–21) | ↑ Sociability in early adulthood in both sexes; ↑ Social novelty in both sexes (1 µg/kg/d); ↓ Social interaction in middle-aged males (1 µg/kg/d) | [89] |
Rat (Sprague-Dawley) | A1221 | 1 mg/kg | Injection (i.p.) | Prenatal (GD 16, 18, 20), Postnatal 1 (PND 24, 26, 28) | ↑ USV calls in female (prenatal and postnatal); ↑ Affiliative wrestling behavior in female (prenatal and postnatal); ↓ Time spent near novel animal of opposite sex in males exposed postnatally | [90] |
Rat (Sprague-Dawley) | A1221 | 0.5 mg/kg, 1 mg/kg | Injection (i.p.) | Prenatal (GD 16, 18) | ↓ Social interaction with novel conspecific in 0.5 mg/kg males | [91] |
Rat (Sprague-Dawley) | A1221 | 0.5 mg/kg/d, 1 mg/kg/d | Injection (i.p.) | Prenatal (GD 16, 18) | ↑ USV calls in males in sociosexual context; No effect on sociosexual behavior in females; ↓ Sociosexual interaction (nose-nose sniffs) in males | [92] |
Rat (Sprague-Dawley) | Mixture (PCBs 47, 77) | 12.5 mg/kg/d, 25 mg/kg/d | Dietary (chow) | Prenatal (GD 0-PND 0), Lactation (PND 0–21) | ↓ Social recognition in 25 mg/kg males; ↓ Social investigation in males (both doses) | [93] |
Model | Exposure | Dose(s) | Route of Exposure | Exposure Window | Findings | Ref. |
---|---|---|---|---|---|---|
Mouse (ICR) | A1254 | 6 mg/kg/d, 8 mg/kg/d | Gavage | Lactation (PND 7–21), Juvenile (PND 22–42) | ↓ NOR performance in females; No effect on alternation behavior in either sex | [74] |
Mouse (ICR) | A1254 | 18 mg/kg/d | Injection (i.p.) | Prenatal (GD 6-PND 0), Lactation (PND 0–21), Postnatal (PND 21–35) | ↓ Object-based attention in NOR task; ↓ Latency to enter open arms of EPM; ↑ Time spent in open arms of EPM | [75] |
Mouse (Swiss albino) | NDL PCB mixture (PCBs 28, 52, 101, 138, 153, 180) | 1 ng/kg/d, 10 ng/kg/d, 100 ng/kg/d | Gavage | Lactation (PND 0–21) | ↑ Escape latency in water escape task in males (1 and 100 ng/kg), ↑ Anxiety-like behavior in EPM and LDB tasks (1 and 10 ng/kg), No effect on performance in MWM task | [76] |
Mouse (Swiss albino) | NDL PCB mixture (PCBs 28, 52, 101, 138, 153, 180) | 10 ng/kg/d | Gavage | Lactation (PND 0–21) | No effect on short-term memory in spontaneous alternation task; No effect on learning acquisition in MWM task | [97] |
Rat (Sprague-Dawley) | A1221 | 1 mg/kg/d | Injection (i.p.) | Prenatal (GD 16, 18, 20), Postnatal 1 (PND 24, 26, 28) | ↑ Entries into and time spent in open arms of EPM in females during both periods | [90] |
Rat (Long-Evans) | Fox River | 3 mg/kg/d, 6 mg/kg/d | Dietary (cookie) | Pre-conception (28 d), Prenatal (GD 0-PND 0), Lactation (PND 0–21) | ↓ DRL performance in 3 mg/kg females; ↓ Inhibitory control in both sexes (both doses) | [98] |
Rat (Long-Evans) | Fox River | 3 mg/kg/d, 6 mg/kg/d | Dietary (cookie) | Postnatal 1 (PND 27–50) | ↑ Response latency in cue discrimination phase of set-shifting task in males (3 mg/kg/d); ↓ Errors to criterion in position reversal in males (both doses); ↓ Perseverative errors in position reversal in males (both doses); No effect on DRL performance | [99] |
Rat (Wistar) | PCB 52, PCB 138, PCB 180 | 1 mg/kg/d | Dietary (jelly) | Prenatal (GD 7-PND 0), Lactation (PND 0–21) | ↓ Learning in Y maze visual discrimination task for PCB 138 and 180 in both sexes | [79] |
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Klocke, C.; Lein, P.J. Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity. Int. J. Mol. Sci. 2020, 21, 1013. https://doi.org/10.3390/ijms21031013
Klocke C, Lein PJ. Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity. International Journal of Molecular Sciences. 2020; 21(3):1013. https://doi.org/10.3390/ijms21031013
Chicago/Turabian StyleKlocke, Carolyn, and Pamela J. Lein. 2020. "Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity" International Journal of Molecular Sciences 21, no. 3: 1013. https://doi.org/10.3390/ijms21031013