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.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.766802 ◽

2021 ◽

Vol 15 ◽

Cited By ~ 1

Author(s):

Kimberly P. Keil Stietz ◽

Sunjay Sethi ◽

Carolyn R. Klocke ◽

Tryssa E. de Ruyter ◽

Machelle D. Wilson ◽

...

Keyword(s):

Polychlorinated Biphenyls ◽

Brain Region ◽

Cortical Neurons ◽

Dose Group ◽

Pyramidal Neurons ◽

Dendritic Arborization ◽

Dependent Manner ◽

Developmental Exposure ◽

The Impact ◽

Pcb Exposure

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.

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Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats

Translational Psychiatry ◽

10.1038/s41398-020-00978-0 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Elizabeth L. Berg ◽

Lauren R. Pedersen ◽

Michael C. Pride ◽

Stela P. Petkova ◽

Kelley T. Patten ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Behavioral Phenotypes ◽

Developmental Exposure ◽

Juvenile Rats

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Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model

Nutrients ◽

10.3390/nu11051187 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1187 ◽

Cited By ~ 9

Author(s):

Asad Ali ◽

Svetlina Vasileva ◽

Mia Langguth ◽

Suzanne Alexander ◽

Xiaoying Cui ◽

...

Keyword(s):

Vitamin D ◽

Animal Model ◽

Social Interaction ◽

Motor Development ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Ultrasonic Vocalizations ◽

Increased Risk

Emerging evidence suggests that gestational or developmental vitamin D (DVD) deficiency is associated with an increased risk of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impairments in social interaction, lack of verbal and non-verbal communications, stereotyped repetitive behaviors and hyper-activities. There are several other clinical features that are commonly comorbid with ASD, including olfactory impairments, anxiety and delays in motor development. Here we investigate these features in an animal model related to ASD—the DVD-deficient rat. Compared to controls, both DVD-deficient male and female pups show altered ultrasonic vocalizations and stereotyped repetitive behavior. Further, the DVD-deficient animals had delayed motor development and impaired motor control. Adolescent DVD-deficient animals had impaired reciprocal social interaction, while as adults, these animals were hyperactive. The DVD-deficient model is associated with a range of behavioral features of interest to ASD.

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Genetic architecture of reciprocal social behavior in toddlers: Implications for heterogeneity in the early origins of autism spectrum disorder

Development and Psychopathology ◽

10.1017/s0954579420000723 ◽

2020 ◽

Vol 32 (4) ◽

pp. 1190-1205

Author(s):

Natasha Marrus ◽

Julia D. Grant ◽

Brooke Harris-Olenak ◽

Jordan Albright ◽

Drew Bolster ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Genetic Architecture ◽

Ethnically Diverse ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Genetic Influences ◽

Heritable Trait ◽

Birth Registries

AbstractImpairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism's heterogeneity.

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Paternal smoking is associated with an increased risk of pregnancy loss in a dose-dependent manner: a systematic review and meta-analysis

F&S Reviews ◽

10.1016/j.xfnr.2021.06.001 ◽

2021 ◽

Author(s):

Nadia A. du Fossé ◽

Marie-Louise P. van der Hoorn ◽

Nina H. Buisman ◽

Jan M.M. van Lith ◽

S askia le Cessie ◽

...

Keyword(s):

Systematic Review ◽

Pregnancy Loss ◽

Meta Analysis ◽

Dependent Manner ◽

Increased Risk ◽

Dose Dependent ◽

Paternal Smoking

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The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

Brain Sciences ◽

10.3390/brainsci11030344 ◽

2021 ◽

Vol 11 (3) ◽

pp. 344

Author(s):

Kinga Gzielo ◽

Agnieszka Potasiewicz ◽

Ewa Litwa ◽

Diana Piotrowska ◽

Piotr Popik ◽

...

Keyword(s):

Immune Activation ◽

Social Play ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Rats ◽

Poly I:C ◽

Maternal Immune Activation ◽

Increased Risk ◽

Adolescent Rats ◽

The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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Actionable and incidental neuroradiological findings in twins with neurodevelopmental disorders

Scientific Reports ◽

10.1038/s41598-020-79959-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Lynnea Myers ◽

Mai-Lan Ho ◽

Elodie Cauvet ◽

Karl Lundin ◽

Torkel Carlsson ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number Variants ◽

Cross Sectional Study ◽

Autism Spectrum ◽

Molecular Signaling ◽

Mri Findings ◽

Cross Sectional ◽

Increased Risk ◽

Magnetic Resonance Imaging Mri ◽

Morphological Variants

AbstractWhile previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

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P125: Low dose intravenous ketorolac in renal colic, a pilot randomized controlled trial

CJEM ◽

10.1017/cem.2020.330 ◽

2020 ◽

Vol 22 (S1) ◽

pp. S109-S110

Author(s):

J. Chao ◽

P. Brasher ◽

K. Cheung ◽

R. Sharma ◽

K. Badke ◽

...

Keyword(s):

Dose Group ◽

Low Dose ◽

Renal Colic ◽

Standard Dose ◽

Controlled Trial ◽

Pain Reduction ◽

Primary Objective ◽

Recruitment Rate ◽

Convenience Sample ◽

Increased Risk

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are first-line analgesics for emergency department (ED) patients with renal colic. Lower doses of intravenous (IV) ketorolac may provide similar pain relief to standard dosing in patients with acute pain. Patients with renal colic may be at increased risk of acute kidney injury; exposing them to lower doses of NSAIDs may put them at lower risk while providing equally effective analgesia. We conducted a pilot study to determine the feasibility of a randomized trial comparing the effectiveness and safety of low with standard ketorolac dosing in ED patients with suspected renal colic. The primary objective was to demonstrate the ability to achieve an enrolment target of 2 patients per week. Methods: We enrolled a convenience sample of adults presenting to an academic urban ED with unilateral flank pain suspected to be renal colic. We randomized patients to 10 mg (low dose, intervention) or 30 mg (standard dose, control). Participants, treating physicians and nurses, and researchers were blinded to treatment allocation. Our main feasibility outcome was the recruitment rate. Secondary outcomes were changes in pain scores (0-10) at 30 and 120 minutes post-ketorolac administration, vital signs, adverse events and ED length of stay. Results: We approached 82 patients, of whom 47 (57.3%) were eligible. Of these, 36 consented to participating and 30 were randomized. The proportion of screened patients who were enrolled was 36.6% (30/82). We completed enrolment over a 21-week period, with an average recruitment rate of 1.5 patients/week (range 0-4). The average baseline pain score for all participants was 6.9 (SD = 2.1). At 30 minutes post-ketorolac administration, the low dose group had a mean pain reduction of 2.0 points compared to a pain reduction of 1.7 in standard dose group (difference = 0.3, 90% CI: -0.7 to 1.4). Conclusion: These preliminary results support the possibility that low dose ketorolac may be efficacious in this patient population. We did not meet our target recruitment of 2 patients per week as this was primarily due to restricted recruitment hours. To successfully conduct a larger trial, we would need to expand both recruitment hours and the number of sites.

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Developmental exposure to silver nanoparticles leads to long term gut dysbiosis and neurobehavioral alterations

Scientific Reports ◽

10.1038/s41598-021-85919-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhen Lyu ◽

Shreya Ghoshdastidar ◽

Karamkolly R. Rekha ◽

Dhananjay Suresh ◽

Jiude Mao ◽

...

Keyword(s):

Silver Nanoparticles ◽

Body Fat ◽

Repetitive Behaviors ◽

Developmental Exposure ◽

Male And Female ◽

Female Mice ◽

Gut Dysbiosis ◽

Study Results ◽

Wide Range

AbstractDue to their antimicrobial properties, silver nanoparticles (AgNPs) are used in a wide range of consumer products that includes topical wound dressings, coatings for biomedical devices, and food-packaging to extend the shelf-life. Despite their beneficial antimicrobial effects, developmental exposure to such AgNPs may lead to gut dysbiosis and long-term health consequences in exposed offspring. AgNPs can cross the placenta and blood–brain-barrier to translocate in the brain of offspring. The underlying hypothesis tested in the current study was that developmental exposure of male and female mice to AgNPs disrupts the microbiome–gut–brain axis. To examine for such effects, C57BL6 female mice were exposed orally to AgNPs at a dose of 3 mg/kg BW or vehicle control 2 weeks prior to breeding and throughout gestation. Male and female offspring were tested in various mazes that measure different behavioral domains, and the gut microbial profiles were surveyed from 30 through 120 days of age. Our study results suggest that developmental exposure results in increased likelihood of engaging in repetitive behaviors and reductions in resident microglial cells. Echo-MRI results indicate increased body fat in offspring exposed to AgNPs exhibit. Coprobacillus spp., Mucispirillum spp., and Bifidobacterium spp. were reduced, while Prevotella spp., Bacillus spp., Planococcaceae, Staphylococcus spp., Enterococcus spp., and Ruminococcus spp. were increased in those developmentally exposed to NPs. These bacterial changes were linked to behavioral and metabolic alterations. In conclusion, developmental exposure of AgNPs results in long term gut dysbiosis, body fat increase and neurobehavioral alterations in offspring.

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