TY - JOUR
T1 - The influence of sex, genotype, and dose on serum and hippocampal cytokine levels in juvenile mice developmentally exposed to a human-relevant mixture of polychlorinated biphenyls
AU - Matelski, Lauren
AU - Keil Stietz, Kimberly P.
AU - Sethi, Sunjay
AU - Taylor, Sandra L.
AU - Van de Water, Judy
AU - Lein, Pamela J.
N1 - Funding Information:
This work was supported by funding from the National Institute of Environmental Health Sciences [ R01 ES014901 to PJL, T32 ES007059 to SS, P01 ES011269 to JV and PJL, and R00 ES029537 to KPKS], the National Institute of Child Health and Human Development [ U54 HD079125 to JV and PJL], and the United States Environmental Protection Agency [ RD83543201 to JV and PJL]. The funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article of publication.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/6/10
Y1 - 2020/6/10
N2 - Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants implicated as risk factors for neurodevelopmental disorders (NDDs). Immune dysregulation is another NDD risk factor, and developmental PCB exposures are associated with early life immune dysregulation. Studies of the immunomodulatory effects of PCBs have focused on the higher-chlorinated congeners found in legacy commercial mixtures. Comparatively little is known about the immune effects of contemporary, lower-chlorinated PCBs. This is a critical data gap given recent reports that lower-chlorinated congeners comprise >70% of the total PCB burden in serum of pregnant women enrolled in the MARBLES study who are at increased risk for having a child with an NDD. To examine the influence of PCBs, sex, and genotype on cytokine levels, mice were exposed throughout gestation and lactation to a PCB mixture in the maternal diet, which was based on the 12 most abundant PCBs in sera from MARBLES subjects. Using multiplex array, cytokines were quantified in the serum and hippocampus of weanling mice expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I mice), a human CGG premutation repeat expansion in the fragile X mental retardation gene 1 (CGG mice), or both mutations (DM mice). Congenic wildtype (WT) mice were used as controls. There were dose-dependent effects of PCB exposure on cytokine concentrations in the serum but not hippocampus. Differential effects of genotype were observed in the serum and hippocampus. Hippocampal cytokines were consistently elevated in T4826I mice and also in WT animals for some cytokines compared to CGG and DM mice, while serum cytokines were usually elevated in the mutant genotypes compared to the WT group. Males had elevated levels of 19 cytokines in the serum and 4 in the hippocampus compared to females, but there were also interactions between sex and genotype for 7 hippocampal cytokines. Only the chemokine CCL5 in the serum showed an interaction between PCB dose, genotype, and sex. Collectively, these findings indicate differential influences of PCB exposure and genotype on cytokine levels in serum and hippocampal tissue of weanling mice. These results suggest that developmental PCB exposure has chronic effects on baseline serum, but not hippocampal, cytokine levels in juvenile mice.
AB - Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants implicated as risk factors for neurodevelopmental disorders (NDDs). Immune dysregulation is another NDD risk factor, and developmental PCB exposures are associated with early life immune dysregulation. Studies of the immunomodulatory effects of PCBs have focused on the higher-chlorinated congeners found in legacy commercial mixtures. Comparatively little is known about the immune effects of contemporary, lower-chlorinated PCBs. This is a critical data gap given recent reports that lower-chlorinated congeners comprise >70% of the total PCB burden in serum of pregnant women enrolled in the MARBLES study who are at increased risk for having a child with an NDD. To examine the influence of PCBs, sex, and genotype on cytokine levels, mice were exposed throughout gestation and lactation to a PCB mixture in the maternal diet, which was based on the 12 most abundant PCBs in sera from MARBLES subjects. Using multiplex array, cytokines were quantified in the serum and hippocampus of weanling mice expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I mice), a human CGG premutation repeat expansion in the fragile X mental retardation gene 1 (CGG mice), or both mutations (DM mice). Congenic wildtype (WT) mice were used as controls. There were dose-dependent effects of PCB exposure on cytokine concentrations in the serum but not hippocampus. Differential effects of genotype were observed in the serum and hippocampus. Hippocampal cytokines were consistently elevated in T4826I mice and also in WT animals for some cytokines compared to CGG and DM mice, while serum cytokines were usually elevated in the mutant genotypes compared to the WT group. Males had elevated levels of 19 cytokines in the serum and 4 in the hippocampus compared to females, but there were also interactions between sex and genotype for 7 hippocampal cytokines. Only the chemokine CCL5 in the serum showed an interaction between PCB dose, genotype, and sex. Collectively, these findings indicate differential influences of PCB exposure and genotype on cytokine levels in serum and hippocampal tissue of weanling mice. These results suggest that developmental PCB exposure has chronic effects on baseline serum, but not hippocampal, cytokine levels in juvenile mice.
KW - CGG repeat expansion mutation
KW - Chemokines
KW - fmr1
KW - Neurodevelopmental disorders
KW - Neuroimmune interactions
KW - Ryanodine receptor
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U2 - 10.1016/j.crtox.2020.09.001
DO - 10.1016/j.crtox.2020.09.001
M3 - Article
AN - SCOPUS:85099976935
VL - 1
SP - 85
EP - 103
JO - Current Research in Toxicology
JF - Current Research in Toxicology
SN - 2666-027X
ER -