A systematic evidence map for the evaluation of noncancer health effects and exposures to polychlorinated biphenyl mixtures.

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

Developmental Exposure to a Human-Relevant Polychlorinated Biphenyl Mixture Causes Behavioral Phenotypes That Vary by Sex and Genotype in Juvenile Mice Expressing Human Mutations That Modulate Neuronal Calcium.

Polychlorinated biphenyls (PCBs) are putative environmental risks for neurodevelopmental disorders. Here, we tested two hypotheses: (1) developmental exposure to a human-relevant PCB mixture causes behavioral phenotypes relevant to neurodevelopmental disorders; and (2) expression of human mutations that dysregulate neuronal Ca2+ homeostasis influence sensitivity to behavioral effects of developmental PCB exposures. To test these hypotheses, we used mice that expressed a gain-of-function mutation (T4826I) in ryanodine receptor 1 (RYR1), the X-linked fragile X mental retardation 1 (FMR1) CGG repeat expansion or both mutations (double mutant; DM). Transgenic mice and wildtype (WT) mice were exposed to the MARBLES PCB mix at 0, 0.1, 1, and 6 mg/kg/day in the maternal diet throughout gestation and lactation. The MARBLES PCB mix simulates the relative proportions of the 12 most abundant PCB congeners found in the serum of pregnant women at increased risk for having a child with a neurodevelopmental disorder. We assessed ultrasonic vocalizations at postnatal day 7 (P7), spontaneous repetitive behaviors at P25-P30, and sociability at P27-P32. Developmental PCB exposure reduced ultrasonic vocalizations in WT litters in all dose groups, but had no effect on ultrasonic vocalizations in transgenic litters. Developmental PCB exposure significantly increased self-grooming and decreased sociability in WT males in the 0.1 mg/kg dose group, but had no effect on WT females in any dose group. Genotype alone influenced ultrasonic vocalizations, self-grooming and to a lesser extent sociability. Genotype alone also influenced effects of PCBs on sociability. PCB levels in the brain tissue of pups increased in a dose-dependent manner, but within any dose group did not differ between genotypes. In summary, developmental PCB exposure phenocopied social behavior phenotypes observed in mice expressing human mutations that modify intracellular Ca2+ dynamics, and expression of these mutations alleviated PCB effects on ultrasonic vocalizations and repetitive behavior, and modified the dose-response relationships and sex-dependent effects of PCB effects on social behavior. These findings suggest that: (1) developmental PCB exposure causes behavioral phenotypes that vary by sex and genotype; and (2) sex-specific responses to environmental factors may contribute to sex biases in the prevalence and/or severity of neurodevelopmental disorders.

Sex and Genotype Modulate the Dendritic Effects of Developmental Exposure to a Human-Relevant Polychlorinated Biphenyls Mixture in the Juvenile Mouse.

While many neurodevelopmental disorders (NDDs) are thought to result from interactions between environmental and genetic risk factors, the identification of specific gene-environment interactions that influence NDD risk remains a critical data gap. We tested the hypothesis that polychlorinated biphenyls (PCBs) interact with human mutations that alter the fidelity of neuronal Ca2+ signaling to confer NDD risk. To test this, we used three transgenic mouse lines that expressed human mutations known to alter Ca2+ signals in neurons: (1) gain-of-function mutation in ryanodine receptor-1 (T4826I-RYR1); (2) CGG-repeat expansion in the 5' non-coding portion of the fragile X mental retardation gene 1 (FMR1); and (3) a double mutant (DM) that expressed both mutations. Transgenic and wildtype (WT) mice were exposed throughout gestation and lactation to the MARBLES PCB mix at 0.1, 1, or 6 mg/kg in the maternal diet. The MARBLES mix simulates the relative proportions of the twelve most abundant PCB congeners found in serum from pregnant women at increased risk for having a child with an NDD. Using Golgi staining, the effect of developmental PCB exposure on dendritic arborization of pyramidal neurons in the CA1 hippocampus and somatosensory cortex of male and female WT mice was compared to pyramidal neurons from transgenic mice. A multilevel linear mixed-effects model identified a main effect of dose driven by increased dendritic arborization of cortical neurons in the 1 mg/kg PCB dose group. Subsequent analyses with genotypes indicated that the MARBLES PCB mixture had no effect on the dendritic arborization of hippocampal neurons in WT mice of either sex, but significantly increased dendritic arborization of cortical neurons of WT males in the 6 mg/kg PCB dose group. Transgene expression increased sensitivity to the impact of developmental PCB exposure on dendritic arborization in a sex-, and brain region-dependent manner. In conclusion, developmental exposure to PCBs present in the gestational environment of at-risk humans interfered with normal dendritic morphogenesis in the developing mouse brain in a sex-, genotype- and brain region-dependent manner. Overall, these observations provide proof-of-principle evidence that PCBs interact with heritable mutations to modulate a neurodevelopmental outcome of relevance to NDDs.

Disposition of PCB 11 in Mice Following Acute Oral Exposure.

PCB 11 (3,3'-dichloro-biphenyl) is an emerging environmental contaminant that represents a public health concern. Here, we investigated the distribution of PCB 11 and its metabolites in mice exposed orally to PCB 11. PCB 11 tissue levels followed the rank order adipose > lung ∼ muscle > liver > brain > blood 4 h after PCB 11 exposure, which varied from the rank order predicted with a composition-based model. We detected hydroxylated and sulfate metabolites in the liver and sulfate and glucuronide metabolites in serum. These findings lay the groundwork for future toxicity studies with PCB 11.

Iron Deficiency and Iron Excess Differently Affect Dendritic Architecture of Pyramidal Neurons in the Hippocampus of Piglets.

BACKGROUND: Both iron deficiency and overload may adversely affect neurodevelopment. OBJECTIVES: The study assessed how changes in early-life iron status affect iron homeostasis and cytoarchitecture of hippocampal neurons in a piglet model. METHODS: On postnatal day (PD) 1, 30 Hampshire × Yorkshire crossbreed piglets (n = 15/sex) were stratified by sex and litter and randomly assigned to experimental groups receiving low (L-Fe), adequate (A-Fe), or high (H-Fe) levels of iron supplement during the pre- (PD1-21) and postweaning periods (PD22-35). Pigs in the L-Fe, A-Fe, and H-Fe groups orally received 0, 1, and 30 mg Fe · kg weight-1 · d-1 preweaning and were fed a diet containing 30, 125, and 1000 mg Fe/kg postweaning, respectively. Heme indexes were analyzed weekly, and gene and protein expressions of iron regulatory proteins in duodenal mucosa, liver, and hippocampus were analyzed through qRT-PCR and western blot, respectively, on PD35. Hippocampal neurons stained using the Golgi-Cox method were traced and their dendritic arbors reconstructed in 3-D using Neurolucida. Dendritic complexity was quantified using Sholl and branch order analyses. RESULTS: Pigs in the L-Fe group developed iron deficiency anemia (hemoglobin = 8.2 g/dL, hematocrit = 20.1%) on PD35 and became stunted during week 5 with lower final body weight than H-Fe group pigs (6.6 compared with 9.6 kg, P < 0.05). In comparison with A-Fe, H-Fe increased hippocampal ferritin expression by 38% and L-Fe decreased its expression by 52% (P < 0.05), suggesting altered hippocampal iron stores. Pigs in the H-Fe group had greater dendritic complexity in CA1/3 pyramidal neurons than L-Fe group pigs as shown by more dendritic intersections with Sholl rings (P ≤ 0.04) and a greater number of dendrites (P ≤ 0.016). CONCLUSIONS: In piglets, the developing hippocampus is susceptible to perturbations by dietary iron, with deficiency and overload differentially affecting dendritic arborization.