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

Abstract

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.

The Bladder Is a Novel Target of Developmental Polychlorinated Biphenyl Exposure Linked to Increased Inflammatory Cells in the Bladder of Young Mice

“…We identified an increase in macrophages within bladders of mice exposed to the lowest PCB dose which was prevalent in female offspring. This finding is consistent with previous studies which have examined effects of PCBs on serum cytokine and chemokine expression [ 45 ]. Macrophages are capable of secreting various cytokines including tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, IL-8, IL-12, IL-23 as well as chemokines such as CXCL1 and 2, CCL5, CXCL8-11 [ 71 ].…”

“…We have previously described the MARBLES PCB mixture and doses selected, 0.1, 1 and 6 mg/kg body weight/day, which result in PCB levels in offspring tissues within ranges observed in humans and do not interfere with reproductive outcomes of the dam [ 32 , 45 , 46 ]. The proportion of individual PCB congeners in the MARBLES PCB mixture mimics the proportion of the top 12 PCB congeners identified in pregnant women at risk of having a child with a neurodevelopmental disorder [ 18 , 28 , 31 ].…”

“…All procedures involving animals were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the University of California-Davis Animal Care and Use Committee (#18853 and 20584; date of approval: 8-5-15 and 8-3-18 respectively). Wild-type mice of 75% C57BL/6J/25% SVJ129 genetic background (Jackson Labs, Sacramento, CA, USA), were used in this study and were collected as part of a larger study as described previously [32,45]. All mice were housed in clear plastic cages containing corn cob bedding and maintained on a 12 h light and dark cycle at 22 ± 2 • C. Feed (Diet 5058, LabDiet, St. Louis, MO, USA) and water were available ad libitum.…”

“…In mice, developmental exposure to MARBLES PCB results in offspring which display alterations in inflammatory markers in the intestine which coincide with changes in intestinal physiology and the microbiota [ 44 ]. In addition, developmental exposure to MARBLES PCB leads to elevated levels of serum cytokines and chemokines in juvenile offspring [ 45 ]. While PCB exposures are linked to changes in circulating cytokines, less is known regarding the inflammatory signature within tissues such as the bladder.…”

Sublethal, sex-specific, osmotic, and metabolic impairments in embryonic and adult round stingrays from a location exposed to environmental contamination in southern California, USA

“…Further challenges arise when contaminant effects are explored in non-model species, as physiological response to contaminant exposure may vary across taxa with different evolutionary histories. Toxicology studies on biochemical responses of contaminant exposure tend to focus on mammalian species, such as rats (Abdel-Daim et al 2020 ; AlBasher et al 2020 ) and mice (AlKahtane et al 2020 ; Matelski et al 2020 ), that serve as well-established models for understanding human health outcomes. However, a paucity of data exists for non-model species such as elasmobranch fishes (sharks, skates, and rays), despite the ecosystem services they provide as predators.…”