Critical windows of susceptibility for the effects of prenatal exposure to heat and heat variability on gestational growth.

BACKGROUND: Studies have shown that prenatal heat exposure may impact fetal growth, but few studies have examined the critical windows of susceptibility. As extreme heat events and within season temperature variability is expected to increase in frequency, it is important to understand how this may impact gestational growth. OBJECTIVES: We investigated associations between various measures of weekly prenatal heat exposure (mean and standard deviation (SD) of temperature and heat index (HI), derived using temperature in °C and dew point) and term birthweight or odds of being born small for gestational age (SGA) to identify critical windows of susceptibility. METHODS: We analyzed data from mother-child dyads (n = 4442) in the Boston-based Children's HealthWatch cohort. Birthweights were collected from survey data and electronic health records. Daily temperature and HI values were obtained from 800 m gridded spatial climate datasets aggregated by the PRISM Climate Group. Distributed lag-nonlinear models were used to assess the effect of the four weekly heat metrics on measures of gestational growth (birthweight, SGA, and birthweight z-scores). Analyses were stratified by child sex and maternal homelessness status during pregnancy. RESULTS: HI variability was significantly associated with decreased term birthweight during gestational weeks 10-29 and with SGA for weeks 9-26. Cumulative effects for these time periods were -287.4 g (95% CI: -474.1 g, -100.8 g for birthweight and 4.7 (95% CI: 1.6, 14.1) for SGA. Temperature variability was also significantly associated with decreased birthweight between weeks 15 and 26. The effects for mean heat measures on term birthweight and SGA were not significant for any gestational week. Stratification by sex revealed a significant effect on term birthweight in females between weeks 23-28 and in males between weeks 9-26. Strongest effects of HI variability on term birthweight were found in children of mothers who experienced homelessness during pregnancy. Weekly HI variability was the heat metric most strongly associated with measures of gestational growth. The effects observed were largest in males and those who experienced homelessness during pregnancy. DISCUSSION: Given the impact of heat variability on birthweight and risk of SGA, it is important for future heat warnings to incorporate measure of heat index and temperature variability.

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals.

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n = 45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine, and phenytoin.

OBJECTIVE: Usage during pregnancy of the antiseizure medication (ASM), phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT), has been associated with adverse pregnancy outcomes. While morphological effects on offspring are well-documented, inconsistent findings have been reported on neuropsychological development, possibly due to differences in attention to maternal demographics, and other design characteristics. Herein, we report the results of a carefully designed protocol used to examine the effects of gestational monotherapy with PB, CBZ, or PHT upon children's general mental abilities, when compared to age- and gender- matched children born to unexposed women of similar age, education, and socioeconomic status. METHODS: For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child's age and gender. Each child's physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children - III (WISC-III), the leading measure of mental ability in the U.S. RESULTS: An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug-drug comparisons. SIGNIFICANCE: These results demonstrate effects on children's mental ability due to prenatal PB exposure, such that analyses adjusted for maternal IQ scores, revealed reduced verbal mental abilities and reduced full-scale IQ scores when scores in exposed children were compared to scores from children of the same age and sex born to demographically similar, healthy unexposed women. When comparisons were made between drug groups, children exposed prenatally to PB performed significantly worse than prenatally PHT-exposed children, but CBZ-exposed children's scores were not significantly different from those of PB or PHT-exposed groups. In light of shared effects on structural teratogenicity, these findings suggest that use of PB monotherapy for the management of seizures during pregnancy may be associated with increased risk in comparison to PHT when neurobehavioral functioning is considered, and that only PB-exposed children have reduced performance compared to matched controls. Attention to these effects is critical in the developing world where use of these older medications remains predominant, and prudent choices can be made to reduce impact on cognitive development.

Urinary Isoflavones Levels in Relation to Serum Thyroid Hormone Concentrations in Female and Male Adults in the U.S. General Population.

Isoflavones are phytoestrogens found in plant-based foods and nutritional supplements. Experimental studies show a positive association between isoflavones and hypothyroidism, but epidemiological findings are conflicting. We used multivariable linear regression to examine the association between urinary isoflavone concentrations and serum thyroid hormone concentrations in the National Health and Nutrition Examination Survey (2007-2010). In this study, we found that Daidzein and O-DMA associations with free T4 were stronger among women: a 10-fold increase in daidzein was associated with a 3.2% (95% CI: 1.9%, 4.5%) increase in women and a 0.6% (95% CI: -1.7%, 0.6%) decrease in men and a 10-fold increase in O-DMA was related to a 2.0% (95% CI: 1.1%, 2.9%) increase in women and a 0.3% (95% CI: -1.2%, 0.5%) decrease in men. In this study, selected urinary isoflavone concentrations were associated with serum thyroid hormone concentration in a sex-dependent fashion.

Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury.

The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning. Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.

Correction to: Occurrence of mental illness following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study.

Following publication of the original article [1], the author reported that, because of a programming error, incorrect sentences and incorrect Table 3 has been published. The correct sentences and Table 3 are shown below.

Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness.

Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI-associated GI and metabolic complications. Results in a GWI-mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin-2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW-chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR-α, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut-4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain.

Temporal trends in air pollution exposure inequality in Massachusetts.

Mounting evidence over the past several decades has demonstrated inequitable distribution of pollutants of ambient origin between sociodemographic groups in the United States. Most environmental inequality studies to date are cross-sectional and used proximity-based methods rather than modeled air pollution concentrations, limiting the ability to examine trends over time or the factors that drive exposure inequalities. In this paper, we use 1km2 modeled PM2.5 and NO2 concentrations in Massachusetts over an 8-year period and Census demographic data to quantify inequality between sociodemographic groups and to develop a more nuanced understanding of the drivers and trends in longitudinal air pollution inequality. Annual-average population-weighted PM2.5 and NO2 concentrations were highest for urban non-Hispanic black populations (11.8µg/m3 in 2003 and 8.4µg/m3 in 2010, vs. 11.3µg/m3 and 8.1µg/m3 for urban non-Hispanic whites) and urban Hispanic populations (15.9 ppb in 2005 and 13.0 ppb in 2010, vs. 13.0 ppb and 10.2 ppb for urban non-Hispanic whites), respectively. While population groups experienced similar absolute decreases in exposure over time, disparities in population-weighted concentrations increased over time when quantified by the Atkinson Index, a relative inequality measure. Exposure inequalities were approximately one order of magnitude greater for NO2 compared to PM2.5, were more pronounced in urban compared to rural geographies, and between racial/ethnic groups compared to income and educational attainment groups. Our results also revealed similar longitudinal PM2.5 and NO2 inequality trends using Census 2000 and Census 2010 data, indicating that spatio-temporal shifts in air pollution may best explain observed trends in inequality. These findings enhance our understanding of factors that contribute to persistent inequalities and underscore the importance of targeted exposure reduction strategies aimed at vulnerable populations and neighborhoods.

Exposure to multiple chemicals in a cohort of reproductive-aged Danish women.

BACKGROUND: Current exposure assessment research does not sufficiently address multi-pollutant exposure and their correlations in human media. Understanding the extent of chemical exposure in reproductive-aged women is of particular concern due to the potential for in utero exposure and fetal susceptibility. OBJECTIVES: The objectives of this study were to characterize concentrations of chemical biomarkers during preconception and examine correlations between and within chemical classes. METHODS: We examined concentrations of 135 biomarkers from 16 chemical classes in blood and urine from 73 women aged 18-40 enrolled in Snart Foraeldre/Milieu, a prospective cohort study of pregnancy planners in Denmark (2011-2014). We compared biomarker concentrations with United States similarly-aged, non-pregnant women who participated in the National Health and Nutrition Environmental Survey (NHANES) and with other international biomonitoring studies. We performed principal component analysis to examine biomarker correlations. RESULTS: The mean number of biomarkers detected in the population was 92 (range: 60-108). The most commonly detected chemical classes were phthalates, metals, phytoestrogens and polycyclic aromatic hydrocarbons. Except blood mercury, urinary barium and enterolactone, geometric means were higher in women from NHANES. Chemical classes measured in urine generally did not load on a single component, suggesting high between-class correlation among urinary biomarkers, while there is high within-class correlation for biomarkers measured in serum and blood. CONCLUSIONS: We identified ubiquitous exposure to multiple chemical classes in reproductive-aged Danish women, supporting the need for more research on chemical mixtures during preconception and early pregnancy. Inter- and intra-class correlation between measured biomarkers may reflect common exposure sources, specific lifestyle factors or shared metabolism pathways.

Self-Reported Traumatic Brain Injury, Health and Rate of Chronic Multisymptom Illness in Veterans From the 1990-1991 Gulf War.

BACKGROUND: Traumatic brain injury (TBI) was not considered to be common in the 1990-1991 Gulf War (GW). Therefore, the relationship between TBI and chronic health symptoms experienced by GW veterans is unknown. Health symptoms reported by veterans deployed more recently to this region (Operations Enduring and Iraqi Freedom) are similar to those of GW veterans and have been primarily attributed to TBI. OBJECTIVE: To examine the relationships among self-reported TBI, health symptoms, chronic multisymptom illness (CMI), and health-related quality of life among GW veterans. PARTICIPANTS: Participants included 1 274 GW veterans from the Devens Cohort Study, 156 of whom self-reported a history of TBI (12.2% of the sample). DESIGN: Cross-sectional retrospective analysis of existing survey data. MAIN MEASURES: A 52-item health symptom checklist and the RAND 36-Item Health short Form Survey. RESULTS: Self-reported TBI in GW Veterans is related to increased rates of health symptoms, CMI, and poorer health-related quality of life. CONCLUSIONS: Gulf War veterans' self-reported exposure to TBI is related to increased rates of chronic health symptoms and CMI, which interfere with everyday activities of daily living.

Long-term health effects of early life exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study.

BACKGROUND: While adult exposure to PCE is known to have toxic effects, there is little information on the long-term impact of prenatal and early childhood exposure. We undertook a retrospective cohort study to examine the effects of their early life exposure to PCE-contaminated drinking water. This retrospective cohort study examined whether prenatal and early childhood exposure to PCE-contaminated drinking water influenced the risk of a variety of chronic conditions among adults who were born between 1969 and 1983 in the Cape Cod area of Massachusetts. METHODS: Eight hundred and thirty-one participants with prenatal and early childhood PCE exposure and 547 unexposed participants were studied. Individuals completed questionnaires to gather information on demographic characteristics, chronic conditions, and other sources of solvent exposure. The location of residences from birth through 1990 were used to estimate PCE exposure with U.S. EPA's water distribution system modeling software (EPANET) modified to incorporate a leaching and transport model. RESULTS: No associations were observed between early life PCE exposure and current occurrence of obesity, diabetes, cardiovascular disease, hypertension, color blindness, near- and far sightedness and dry eyes. In contrast, a 1.8-fold increased risk of cancer (95% CI: 0.8, 4.0) was seen among individuals with any early life exposure. These results were based on 31 participants (23 exposed and 8 unexposed) who reported cancers at a variety of anatomical sites, particularly the cervix. A 1.5-fold increase in the risk of epilepsy (95% CI: 0.6, 3.6, based on 16 exposed and 7 unexposed participants) was also observed among individuals with any early life exposure that was further increased to 1.8 (95% CI: 0.7, 4.6) among those with exposure at or above the sample median. CONCLUSIONS: These results suggest that the risk of epilepsy and certain types of cancer such as cervical cancer may be increased among adults who were exposed to PCE-contaminated drinking water exposure during gestation and early childhood. These findings should be interpreted cautiously because of the study limitations and confirmed in follow-up investigations of similarly exposed populations with medically-confirmed diagnoses. This relatively young study population should also be monitored periodically for subsequent changes in disease risk.

School Greenness and Student-Level Academic Performance: Evidence From the Global South.

Greenspace in schools might enhance students' academic performance. However, the literature-dominated by ecological studies at the school level in countries from the Northern Hemisphere-presents mixed evidence of a beneficial association. We evaluated the association between school greenness and student-level academic performance in Santiago, Chile, a capital city of the Global South. This cross-sectional study included 281,695 fourth-grade students attending 1,498 public, charter, and private schools in Santiago city between 2014 and 2018. Student-level academic performance was assessed using standardized test scores and indicators of attainment of learning standards in mathematics and reading. School greenness was estimated using Normalized Difference Vegetation Index (NDVI). Linear and generalized linear mixed-effects models were fit to evaluate associations, adjusting for individual- and school-level sociodemographic factors. Analyses were stratified by school type. In fully adjusted models, a 0.1 increase in school greenness was associated with higher test scores in mathematics (36.9 points, 95% CI: 2.49; 4.88) and in reading (1.84 points, 95% CI: 0.73; 2.95); as well as with higher odds of attaining learning standards in mathematics (OR: 1.20, 95% CI: 1.12; 1.28) and reading (OR: 1.07, 95% CI: 1.02; 1.13). Stratified analysis showed differences by school type, with associations of greater magnitude and strength for students attending public schools. No significant associations were detected for students in private schools. Higher school greenness was associated with improved individual-level academic outcomes among elementary-aged students in a capital city in South America. Our results highlight the potential of greenness in the school environment to moderate educational and environmental inequalities in urban areas.

The CTIS Womb to Classroom Screening Program for the detection of agents with adverse effects on neuropsychological development.

Over the last several decades, federal agencies engaged in the screening of environmental or pharmaceutical agents have recognized the need to conduct research in animal models to identify agents that have classic teratogenic effects as well as effects on neural and behavioral development. Many questions typically addressed in rodent models can be further addressed using real-world, everyday human exposures. Although some postmarketing surveillance programs have been put in place to examine the influences on birth characteristics, it is now urgent that programs be launched to examine the long-term risks associated with exposure to the many medications, drugs, and environmental chemicals for which data are currently unavailable and unexplored. The California Teratogen Information Service (CTIS), established in 1983, and its corresponding Clinical Research Program represent the oldest national program directed at identifying pregnancy risk factors and exposures associated with adverse pregnancy outcome, including behavioral dysfunction. In recognition of the rising rates of developmental disorders involving compromised mental ability, in 2007, CTIS committed to the development of a more comprehensive screening program designed to detect relationships between adverse prenatal exposures and compromised human neurobehavioral development. The "CTIS Womb to Classroom Screening Program for the Detection of Agents with Adverse Effects on Neuropsychological Development" is the first program designed to identify agents not yet known to be of concern.

Occurrence of mental illness following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study.

BACKGROUND: While many studies of adults with solvent exposure have shown increased risks of anxiety and depressive disorders, there is little information on the impact of prenatal and early childhood exposure on the subsequent risk of mental illness. This retrospective cohort study examined whether early life exposure to tetrachloroethylene (PCE)-contaminated drinking water influenced the occurrence of depression, bipolar disorder, post-traumatic stress disorder, and schizophrenia among adults from Cape Cod, Massachusetts. METHODS: A total of 1,512 subjects born between 1969 and 1983 were studied, including 831 subjects with both prenatal and early childhood PCE exposure and 547 unexposed subjects. Participants completed questionnaires to gather information on mental illnesses, demographic and medical characteristics, other sources of solvent exposure, and residences from birth through 1990. PCE exposure originating from the vinyl-liner of water distribution pipes was assessed using water distribution system modeling software that incorporated a leaching and transport algorithm. RESULTS: No meaningful increases in risk ratios (RR) for depression were observed among subjects with prenatal and early childhood exposure (RR: 1.1, 95% CI: 0.9-1.4). However, subjects with prenatal and early childhood exposure had a 1.8-fold increased risk of bipolar disorder (N = 36 exposed cases, 95% CI: 0.9-1.4), a 1.5-fold increased risk post-traumatic stress disorder (N = 47 exposed cases, 95% CI: 0.9-2.5), and a 2.1-fold increased risk of schizophrenia (N = 3 exposed cases, 95% CI: 0.2-20.0). Further increases in the risk ratio were observed for bipolar disorder (N = 18 exposed cases, RR; 2.7, 95% CI: 1.3-5.6) and post-traumatic stress disorder (N = 18 exposed cases, RR: 1.7, 95% CI: 0.9-3.2) among subjects with the highest exposure levels. CONCLUSIONS: The results of this study provide evidence against an impact of early life exposure to PCE on the risk of depression. In contrast, the results provide support for an impact of early life exposure on the risk of bipolar disorder and post-traumatic stress disorder. The number of schizophrenia cases was too small to draw reliable conclusions. These findings should be confirmed in investigations of other similarly exposed populations.

Pre-pregnancy body mass index and parent and teacher-reported behavioral outcomes among offspring in childhood.

OBJECTIVE: Pre-pregnancy obesity has been linked to childhood neurodevelopmental outcomes, including autism and attention-deficit hyperactivity disorder. The aim of our study was to examine the association between pre-pregnancy body mass index (BMI) and scores on behavioral scales according to both mother and teacher report. METHODS: We conducted a longitudinal study of 469 mother-child pairs. Information on pre-pregnancy body mass index (BMI) was collected from standardized maternal interviews conducted after delivery and assessment of childhood behavioral problems was measured at 5-12 years of age according to maternal-report using the Child Behavior Checklist (CBCL) and teacher-report using the Teacher Report Form (TRF). Using normal pre-pregnancy BMI (18.5-24.9 kg/m2) as the reference (n = 305), we calculated adjusted mean differences (MD) for t-scores on broadband and syndrome scales of behavior for children of mothers with pre-pregnancy overweight (n = 101) or obese (n = 63) BMI. We also examined associations with scores in the clinical range using risk ratios (RR) and compared results across informants. To account for loss to follow-up between the initial interview and the childhood behavioral assessment, we weighted models using stabilized inverse probability weights. RESULTS: Pre-pregnancy obesity was associated with a mean increase in child's total behavior problem t-scores according to both mother and teacher report, after adjustment for confounders and weighted for loss to follow-up (MD: 0.7, 95% CI: -2.2, 3.6 on CBCL; MD: 3.1, 95% CI: 0.5, 5.7 on TRF), indicating poorer behavioral outcomes. Comparing the magnitude of associations between mother and teacher-report, mean differences for pre-pregnancy obesity and most behavioral problem scales were larger for teacher-reported outcomes than mother-reported outcomes. Pre-pregnancy obesity was associated with increased risks of externalizing behaviors in the clinical range regardless of informant (CBCL RR: 1.6, 95% CI: 0.8, 3.2 and TRF RR: 1.7, 95% CI: 0.8, 3.5). Pre-pregnancy obesity was also associated with increased risks of internalizing behaviors according to teacher-report (TRF RR: 2.6, 95% CI:1.5, 4.6). CONCLUSIONS: Pre-pregnancy obesity, compared to pre-pregnancy normal weight, is associated with generally higher scores on both mother and teacher reported childhood behavioral assessments, indicating an increased likelihood of behavioral problems.

Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation.

Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resistance to a wide class of antibiotics and exhibited an array of mobile genetic elements (MGEs) distinct from normal healthy controls. The altered resistome and gene signature is correlated with mouse serum IL-6 levels. Altered resistome in mice also is correlated strongly with intestinal inflammation, decreased synaptic plasticity, reversible with fecal microbiota transplant (FMT). The results reported might help in understanding the risks to treating hospital acquired infections in this population.

Affinity for risky behaviors following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study.

BACKGROUND: Many studies of adults with acute and chronic solvent exposure have shown adverse effects on cognition, behavior and mood. No prior study has investigated the long-term impact of prenatal and early childhood exposure to the solvent tetrachloroethylene (PCE) on the affinity for risky behaviors, defined as smoking, drinking or drug use as a teen or adult. OBJECTIVES: This retrospective cohort study examined whether early life exposure to PCE-contaminated drinking water influenced the occurrence of cigarette smoking, alcohol consumption, and drug use among adults from Cape Cod, Massachusetts. METHODS: Eight hundred and thirty-one subjects with prenatal and early childhood PCE exposure and 547 unexposed subjects were studied. Participants completed questionnaires to gather information on risky behaviors as a teenager and young adult, demographic characteristics, other sources of solvent exposure, and residences from birth through 1990. PCE exposure was estimated using the U.S. EPA's water distribution system modeling software (EPANET) that was modified to incorporate a leaching and transport model to estimate PCE exposures from pipe linings. RESULTS: Individuals who were highly exposed to PCE-contaminated drinking water during gestation and early childhood experienced 50-60% increases in the risk of using two or more major illicit drugs as a teenager or as an adult (Relative Risk (RR) for teen use = 1.6, 95% CI: 1.2-2.2; and RR for adult use = 1.5, 95% CI: 1.2-1.9). Specific drugs for which increased risks were observed included crack/cocaine, psychedelics/hallucinogens, club/designer drugs, Ritalin without a prescription, and heroin (RRs:1.4-2.1). Thirty to 60% increases in the risk of certain smoking and drinking behaviors were also seen among highly exposed subjects. CONCLUSIONS: The results of this study suggest that risky behaviors, particularly drug use, are more frequent among adults with high PCE exposure levels during gestation and early childhood. These findings should be confirmed in follow-up investigations of other exposed populations.

Perchloroethylene and Dry Cleaning: It's Time to Move the Industry to Safer Alternatives.

Perchloroethylene (PERC) is the most common solvent used for dry cleaning in the United States. PERC is a reproductive toxicant, neurotoxicant, potential human carcinogen, and a persistent environmental pollutant. The Environmental Protection Agency is evaluating PERC under the Frank R. Lautenberg Chemical Safety for the 21st Century Act, which amended the Toxic Substances Control Act (amended TSCA), and has mandated that PERC dry cleaning machines be removed from residential buildings. Some local and state programs are also requiring or facilitating transitions to alternative cleaning technologies. However, the potential for these alternatives to harm human health and the environment is not well-understood. This review describes the issues surrounding the use of PERC and alternative solvents for dry cleaning while highlighting the lessons learned from a local government program that transitioned PERC dry cleaners to the safest current alternative: professional wet cleaning. Implications for future public health research and policy are discussed: (1) we must move away from PERC, (2) any transition must account for the economic instability and cultural aspects of the people who work in the industry, (3) legacy contamination must be addressed even after safer alternatives are adopted, and (4) evaluations of PERC alternatives are needed to determine their implications for the long-term health and sustainability of the people who work in the industry.

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk.

Gulf War Illness (GWI) is a chronic multi-symptomatic illness that is associated with fatigue, pain, cognitive deficits, and gastrointestinal disturbances and presents a significant challenge to treat in clinics. Our previous studies show a role of an altered Gut-Brain axis pathology in disease development and symptom persistence in GWI. The present study utilizes a mouse model of GWI to study the role of a labdane diterpenoid andrographolide (AG) to attenuate the Gut-Brain axis-linked pathology. Results showed that AG treatment in mice (100 mg/kg) via oral gavage restored bacteriome alterations, significantly increased probiotic bacteria Akkermansia, Lachnospiraceae, and Bifidobacterium, the genera that are known to aid in preserving gut and immune health. AG also corrected an altered virome with significant decreases in virome families Siphoviridae and Myoviridae known to be associated with gastrointestinal pathology. AG treatment significantly restored tight junction proteins that correlated well with decreased intestinal proinflammatory mediators IL-1ß and IL-6 release. AG treatment could restore Claudin-5 levels, crucial for maintaining the BBB integrity. Notably, AG could decrease microglial activation and increase neurotrophic factor BDNF, the key to neurogenesis. Mechanistically, microglial conditioned medium generated from IL-6 stimulation with or without AG in a concentration similar to circulating levels found in the GWI mouse model and co-incubated with neuronal cells in vitro, decreased Tau phosphorylation and neuronal apoptosis. In conclusion, we show that AG treatment mitigated the Gut-Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI.

Brain-Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990-1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990-1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service.