Considerations for deriving a safe intake of propylene glycol.

The use of propylene glycol (PG) in food and other applications is widespread, and some estimates of dietary exposure to PG approach or exceed the Acceptable Daily Intake (ADI) of 25 mg/kg bw-day. The current ADI for PG applies a cumulative uncertainty factor of 100, which includes factors of 10 for both interspecies and intraspecies differences. Available toxicology studies and human data, however, indicate a plausible mode of action (MoA) that would support a chemical-specific adjustment factor (CSAF) of 1 for interspecies toxicodynamic differences, reducing the total uncertainty factor from 100 to 40. The MoA involves an increase in serum PG concentrations after metabolic saturation, leading to serum hyperosmolarity, which can ultimately cause hemolytic changes and red blood cell damage. Therefore, the species similarities in toxicodynamic response for this critical effect could support increasing the ADI from 25 to 62.5 mg/kg bw-day, applicable to both children and adults.

Identification of novel NRF2-dependent genes as regulators of lead and arsenic toxicity in neural progenitor cells.

Lead (Pb) and arsenic (As) are prevalent metal contaminants in the environment. Exposures to these metals are associated with impaired neuronal functions and adverse effects on neurodevelopment in children. However, the molecular mechanisms by which Pb and As impair neuronal functions remain poorly understood. Here, we identified F2RL2, TRIM16L, and PANX2 as novel targets of Nuclear factor erythroid 2-related factor 2 (NRF2)-the master transcriptional factor for the oxidative stress response-that are commonly upregulated with both Pb and As in human neural progenitor cells (NPCs). Using a ChIP (Chromatin immunoprecipitation)-qPCR assay, we showed that NRF2 directly binds to the promoter region of F2RL2, TRIM16L, and PANX2 to regulate expression of these genes. We demonstrated that F2RL2, PANX2, and TRIM16L have differential effects on cell death, proliferation, and differentiation of NPCs in both the presence and absence of metal exposures, highlighting their roles in regulating NPC function. Furthermore, the analyses of the transcriptomic data on NPCs derived from autism spectrum disorder (ASD) patients revealed that dysregulation of F2RL2, TRIM16L, and PANX2 was associated with ASD genetic backgrounds and ASD risk genes. Our findings revealed that Pb and As induce a shared NRF2-dependent transcriptional response in NPCs and identified novel genes regulating NPC function. While further in vivo studies are warranted, this study provides a novel mechanism linking metal exposures to NPC function and identifies potential genes of interest in the context of neurodevelopment.

Adolescence as a sensitive period for neurotoxicity: Lifespan developmental effects of methylmercury.

Neurotoxicity resulting from the environmental contaminant, methylmercury (MeHg), is a source of concern for many human populations that rely heavily on the consumption of fish and rice as stable ingredients in the diet. The developmental period of exposure is important both to the qualitative effects of MeHg and to the dose required to produce those effects. MeHg exposure during the sensitive prenatal period causes deleterious and long-lasting changes in neurodevelopment at particularly low doses. The effects include a wide host of cognitive and behavioral outcomes expressed in adulthood and sometimes not until aging. However, neurotoxic outcomes of MeHg when exposure occurs during adolescence are only recently revealing impacts on human populations and animal models. This review examines the current body of work and showcases the sensitivity of adolescence, a period that straddles early development and adulthood, to MeHg neurotoxicity and the implications such toxicity has in our understanding of MeHg's effects in human populations and animal models.

A review and analysis of personal and ambient PM2.5 measurements: Implications for epidemiology studies.

BACKGROUND: In epidemiology studies, ambient measurements of PM2.5 are often used as surrogates for personal exposures. However, it is unclear the degree to which ambient PM2.5 reflects personal exposures. OBJECTIVE: In order to examine potential sources of bias in epidemiology studies, we conducted a review and meta-analysis of studies to determine the extent to which short-term measurements of ambient PM2.5 levels are related to short-term measurements of personal PM2.5 levels. METHODS: We conducted a literature search of studies reporting both personal and ambient measurements of PM2.5 published in the last 10 years (2009-2019) and incorporated studies published prior to 2009 from reviews. RESULTS: Seventy-one studies were identified. Based on 17 studies reporting slopes, a meta-analysis revealed an overall slope of 0.56 µg/m3 (95% CI: [0.39, 0.73]) personal PM2.5 per µg/m3 increase in ambient PM2.5. Slopes for summer months were higher (slope = 0.73, 95% CI: [0.64, 0.81]) than for winter (slope = 0.46, 95% CI: [0.36, 0.57]). Based on 44 studies reporting correlations, we calculated an overall personal-ambient PM2.5 correlation of 0.63 (95% CI: [0.55, 0.71]). Correlations were stronger in studies conducted in Canada (r = 0.86, 95% CI: [0.67, 0.94]) compared to the USA (r = 0.60, 95% CI: [0.49, 0.70]) and China (r = 0.60, 95% CI: [0.46, 0.71]). Correlations also were stronger in urban areas (r = 0.53, 95% CI: [0.43, 0.62]) vs. suburban areas (r = 0.36, 95% CI: [0.21, 0.49]). SIGNIFICANCE: Our results suggest a large degree of variability in the personal-ambient PM2.5 association and the potential for exposure misclassification and measurement error in PM2.5 epidemiology studies.

Potential implications of new information concerning manganese Ohio community health effects studies.

Several epidemiology studies have been conducted in Ohio communities where industrial facilities with manganese emissions are located. New information not addressed in the published papers for this research has been disclosed by U.S. federal agencies pursuant to the Freedom of Information Act. This paper describes the newly available information, presents statistical analyses of the new summary data, and explores how this information potentially impacts the conclusions of the published research. Based on a statistical analysis of the newly available data, we found very few, and no consistent, statistical differences for various illnesses, self-reported symptoms, and neuropsychological/neuromotor test results between one community with a manganese emission source and a control town that were part of the initial research. Further, we determined that the distribution of total suspended particulate manganese air concentrations did not correlate with the distribution of the more biologically relevant respirable manganese concentrations when data from two communities with potential manganese emissions were combined. These results are important, particularly in determining whether the studies should influence regulatory reference values related to manganese. We recommend that the full health effects data set associated with the published research be made available and re-evaluated to address the issues identified in this paper.

Methylmercury, attention, and memory: baseline-dependent effects of adult d-amphetamine and marginal effects of adolescent methylmercury.

Methylmercury (MeHg) is an environmental neurotoxicant known to disrupt behavior related to dopamine neurotransmission in experimental models. Such disruptions are sensitive to dopamine agonists when administered acutely after exposure to MeHg has ended or when administered concurrently with MeHg exposure. Sustained attention and short-term remembering, components of attention-deficit/hyperactivity disorder (ADHD), are partially mediated by dopamine neurotransmission. In order to observe MeHg-related alterations in sustained attention and short-term memory, as well as determine sensitivity of MeHg exposed animals to dopamine agonists commonly used in the treatment of ADHD symptoms, rats were exposed to 0, 0.5, or 5 ppm MeHg throughout adolescence and trained in a hybrid sustained attention/short term memory visual signal detection task in adulthood. Behavior was then probed with acute i.p. injections of the dopamine agonist, d-amphetamine, which improves impaired attention and inhibits short-term memory in clinical syndromes like ADHD. Acute d-amphetamine dose-dependently decreased short-term memory as well as sustained attention. While MeHg alone did not impair accuracy or memory, it did interact with d-amphetamine to produce baseline-dependent inhibition of behavior. These findings further show that changes in behavior following low-level exposure to MeHg during adolescence are augmented by dopamine agonists. Observed impairments in memory following acute d-amphetamine are consistent with previous findings.

Adolescent methylmercury exposure alters short-term remembering, but not sustained attention, in male Long-Evans rats.

Methylmercury is an environmental neurotoxicant found in fish that produces behavioral deficits following early developmental exposure. The impact of adolescent exposure to this developmental neurotoxicant is only recently being explored in animal models. Here, short-term memory and sustained attention were examined using a rodent model of adolescent methylmercury exposure. Rats were exposed to 0, 0.5, or 5 ppm methylmercury throughout the adolescent period and tested on a two-choice visual signal detection task in adulthood. Methylmercury improved short-term remembering in this procedure but the dose-effect curve was nonmonotonic, as has been reported previously: effects on memory were observed in animals exposed to 0.5 ppm methylmercury, but not 5 ppm. Methylmercury did not significantly alter sustained attention, which is in contrast to effects following gestational exposure in human populations. The results may suggest that attention is not involved with previously reported effects of methylmercury during adolescence, but certain procedural issues remain unresolved.

Behavioral effects of chronic WIN 55,212-2 administration during adolescence and adulthood in mice.

Marijuana, a psychoactive drug that activates cannabinoid-1 (CB1) receptors in the brain, is the most prevalently abused illicit drug among American adolescents and young adults. However, the long-term consequences of adolescent exposure to cannabinoids on the brain and behavior remain poorly understood. In both humans and nonhumans, adolescence is characterized by the maturation of the endocannabinoid neurotransmitter system in the prefrontal cortex and striatum-brain regions that underlie choice and decision making and are densely packed with CB1 receptors. In the current study, the effects of chronic WIN 55,212-2 (a CB1 agonist) exposure during adolescence on reversal learning and delay discounting were compared with those of adult-onset exposure using mice. Mice were administered 3.0 mg/kg/day WIN 55,212-2 or vehicle for 21 days beginning in adolescence (postnatal days 28-49) or adulthood (postnatal days 90-111). For the reversal-learning task, there was no difference in errors or omissions to criterion following a reversal in adolescent-exposed mice but adult-exposed mice showed a delay in beginning the reversal, suggesting that adolescents, but not adults, are resilient to this drug. Adult mice given WIN 55,212-2 in adolescence displayed greater impulsivity in the form of preference for smaller-sooner reinforcers over larger-delayed ones in the delay-discounting procedure, but this was seen to a lesser extent with adult-onset exposure. These data underscore the importance of variables related to the timing and duration of exposure as well as the specific and persistent behavioral endpoints affected by chronic cannabinoid administration. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

d-Amphetamine and methylmercury exposure during adolescence alters sensitivity to monoamine uptake inhibitors in adult mice.

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.

Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice.

Methylmercury (MeHg), an environmental neurotoxicant primarily found in fish, produces neurobehavioral impairment when exposure occurs during gestation. Whether other developmental periods, such as adolescence, display enhanced vulnerability to the behavioral effects of MeHg exposure is only beginning to be explored. Further, little is known about the effects of repeated administration of lysine deacetylase inhibitors, such as sodium butyrate (NaB), on operant behavior. In Experiment 1, male C57BL6/n mice were exposed to 0, 0.3, and 3.0 ppm MeHg (n = 12 each) via drinking water from postnatal days 21 to 60 (murine adolescence). As adults, mice were trained to lever press under an ascending series of fixed-ratio schedules of milk reinforcement selected to enable the analysis of three important parameters of operant behavior using the framework provided by Mathematical Principles of Reinforcement. Adolescent MeHg exposure dose-dependently increased saturation rate, a measure of the retroactive reach of a reinforcer, and decreased minimum response time relative to controls. In Experiment 2, the behavioral effects of repeated NaB administration both alone and following adolescent MeHg exposure were examined. Male C57BL6/n mice were given either 0 or 3.0 ppm MeHg during adolescence and, before behavioral testing, two weeks of once daily i.p. injections of saline or 0.6 g/kg NaB (n = 12 in each cell). Adolescent MeHg exposure again increased saturation rate but did not significantly alter minimum response time. NaB also increased saturation rate in both MeHg exposure groups. These data suggest that the behavioral mechanisms of adolescent MeHg exposure and NaB may be related to the impact of reinforcement on prior responses. Specifically, MeHg and NaB concentrated the effects of reinforcers onto the most recent responses.

Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.

Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice.

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d-amphetamine (d-AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d-AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10-12/group): control, MeHg, d-AMP, and MeHg + d-AMP. MeHg exposure (via drinking water) spanned postnatal days 21-59 (the murine adolescent period), and once daily intraperitoneal injections of d-AMP or saline spanned postnatal days 28-42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following 2 SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d-AMP, and MeHg + d-AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d-AMP exposure. MeHg + d-AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d-AMP administration. (PsycINFO Database Record

High-fat diet alters weight, caloric intake, and haloperidol sensitivity in the context of effort-based responding.

High-fat (HF) diets result in weight gain, hyperphagia, and reduced dopamine D2 signaling; however, these findings have been obtained only under free-feeding conditions. This study tested the extent to which HF diet affects effort-dependent food procurement and the extent to which dopamine signaling is involved. Male Sprague-Dawley rats consumed either a HF (n=20) or a standard-chow (n=20) diet. We assessed the sensitivity to effort-based reinforcement in 10 rats from each group by measuring consumption across a series of fixed-ratio schedules (FR 5-FR 300) under a closed economy and quantified performance using the exponential-demand equation. For each FR, acute injections of 0 or 0.1 mg/kg of haloperidol, a D2 antagonist, were administered to assess dopamine-related changes in consumption. Rats fed a HF diet consumed more calories and weighed significantly more than rats fed standard-chow. Food consumption decreased in both groups in an effort-dependent manner, but there were no group differences. Haloperidol reduced responding in an FR-dependent manner for both groups. Animals exposed to a HF diet showed an altered sensitivity to haloperidol relative to rats fed a standard diet, suggesting that HF diet alters sensitivity to DA signaling underlying effort-based food procurement.

Adolescent methylmercury exposure affects choice and delay discounting in mice.

The developing fetus is vulnerable to low-level exposure to methylmercury (MeHg), an environmental neurotoxicant, but the consequences of exposure during the adolescent period remain virtually unknown. The current experiments were designed to assess the effects of low-level MeHg exposure during adolescence on delay discounting, preference for small, immediate reinforcers over large, delayed ones, using a mouse model. Thirty-six male C57BL/6n mice were exposed to 0, 0.3, or 3.0ppm mercury (as MeHg) via drinking water from postnatal day 21 through 59, encompassing the murine adolescent period. As adults, mice lever pressed for a 0.01-cc droplet of milk solution delivered immediately or four 0.01-cc droplets delivered after a delay. Delays ranged from 1.26 to 70.79s, and all were presented within a session. A model based on the Generalized Matching Law indicated that sensitivity to reinforcer magnitude was lower for MeHg-exposed mice relative to controls, indicating that responding in MeHg-exposed mice was relatively indifferent to the larger reinforcer. Sensitivity to reinforcer delay was reduced (delay discounting was decreased) in the 0.3-ppm group, but not in the 3.0-ppm group, compared to controls. Adolescence is a developmental period during which the brain and behavior may be vulnerable to MeHg exposure. As with gestational MeHg exposure, the effects are reflected in the impact of reinforcing stimuli.

Chronic cocaine exposure in adolescence: Effects on spatial discrimination reversal, delay discounting, and performance on fixed-ratio schedules in mice.

Adolescence is marked by the continued development of the neural pathways that support choice and decision-making, particularly those involving dopamine signaling. Cocaine exposure during adolescence may interfere with this development and manifest as increased perseveration and delay discounting in adulthood, behavioral processes that are related to drug addiction. Adolescent mice were exposed to 30mg/kg/day of cocaine (n=11) or saline vehicle (n=10) for 14days and behavior was assessed in adulthood. In Experiment 1, performance on a spatial-discrimination-reversal procedure was evaluated. In the first two sessions following the first reversal, cocaine-exposed mice produced more preservative errors relative to controls. In Experiment 2, cocaine-exposed mice displayed steeper delay discounting than saline-exposed mice, effects that were reversed by acute cocaine administration. Experiment 3 examined responding maintained by a range of fixed-ratio schedules of reinforcement. An analysis based on a theoretical framework called Mathematical Principles of Reinforcement (MPR) was applied to response-rate functions of individual mice. According to MPR, differences in response-rate functions in adulthood were due to a steepening of the delay-of-reinforcement gradient, disrupted motoric capacity (lower maximum response rates), and enhanced reinforcer efficacy for the adolescent cocaine- compared with saline-exposed mice. Overall, these experiments suggest that chronic exposure to cocaine during adolescence may impair different features of 'executive functions' in adulthood, and these may be related to distortions in the impact of reinforcing events.

Differential associations between obesity and behavioral measures of impulsivity.

A growing literature indicates that impulsivity is a fundamental behavioral process that underlies obesity. However, impulsivity is a multidimensional construct, which comprises independent patterns of decision-making that could be uniquely associated with obesity. No research to date has clarified whether obesity is differentially associated with specific behavioral aspects of impulsivity. This study examined whether obesity was differentially associated with patterns of decision-making associated with impulsivity-delay discounting, probability discounting, and response inhibition. Young adults (n = 296; 44.3% male) age 18-30 were recruited from the community with media advertisements. Participants completed a series of standard self-report measures of health outcomes and behavioral measures of delay discounting, probability discounting, and response inhibition individually in a laboratory. Associations between body mass index (BMI) and behavioral outcomes in the whole sample indicated that BMI was associated with age, delay discounting, and probability discounting, but not response inhibition. A logistic regression that included age, sex, and substance use as covariates found that delay discounting, but neither probability discounting nor response inhibition, was associated with obesity status. Sensitivity to delay, rather than response inhibition and sensitivity to uncertainty, may be the best correlate of obesity status in adults. These findings are relevant to our understanding of the fundamental behavioral processes associated with obesity.

Sensorimotor training during expression of the leg extension response (LER) in 1-day-old rats.

In newborn rats, the leg extension response (LER) is a coordinated hyperextension of the hindlimbs that is shown in response to anogenital stimulation. Here we examined the influence of sensorimotor training on LER expression in postnatal day 1 rats. In Experiment 1, we examined if proprioceptive feedback facilitates LER expression. We did this by repeatedly stimulating the pup's anogenital region with a vibrotactile device, to experimentally evoke the LER, thus increasing LER-relevant hindlimb proprioceptive feedback during training. In trained subjects, the LER was evoked every 4 min for 15 trials, followed by a final LER test. Results indicated that proprioceptive feedback on its own did not alter later expression of the LER. In Experiment 2, we examined the effect of both proprioceptive and cutaneous feedback on LER expression, through the use of a range of motion (ROM) restriction during training. During ROM restriction, a Plexiglas plate was placed beneath the pup at 50% of limb length. After the 15th training trial, a final LER test occurred with no ROM restriction in place. Compared to controls, pups that experienced ROM restriction exhibited a significantly shorter LER duration, and smaller hip and ankle angles during the LER test (indicating greater limb flexion). Together these findings show that concurrent proprioceptive and cutaneous feedback, but not proprioceptive feedback alone, has persistent effects on expression of this newborn action pattern.

Haloperidol and rimonabant increase delay discounting in rats fed high-fat and standard-chow diets.

The dopamine and endocannabinoid neurotransmitter systems have been implicated in delay discounting, a measure of impulsive choice, and obesity. The current study was designed to determine the extent to which haloperidol and rimonabant affected delay discounting in rats fed standard-chow and high-fat diets. Sprague-Dawley rats were allowed to free-feed under a high-fat diet (4.73 kcal/g) or a standard-chow diet (3.0 kcal/g) for 3 months. Then, operant sessions began in which rats (n=9 standard chow; n=10 high-fat) chose between one sucrose pellet delivered immediately versus three sucrose pellets after a series of delays. In another condition, carrot-flavored pellets replaced sucrose pellets. After behavior stabilized, acute injections of rimonabant (0.3-10 mg/kg) and haloperidol (0.003-0.1 mg/kg) were administered intraperitoneally before some choice sessions under both pellet conditions. Haloperidol and rimonabant increased discounting in both groups of rats by decreasing percent choice for the larger reinforcer and area-under-the-curve values. Rats in the high-fat diet condition showed increased sensitivity to haloperidol compared with chow-fed controls; haloperidol increased discounting in both dietary groups in the sucrose condition, but only in the high-fat-fed rats in the carrot-pellet condition. These findings indicate that blocking dopamine-2 and cannabinoid-1 receptors results in increased delay discounting, and that a high-fat diet may alter sensitivity to dopaminergic compounds using the delay-discounting task.