Environmental Chemicals and Autism: A Scoping Review of the Human and Animal Research.

BACKGROUND: Estimates of autism prevalence have increased dramatically over the past two decades. Evidence suggests environmental factors may contribute to the etiology of the disorder. OBJECTIVES: This scoping review aimed to identify and categorize primary research and reviews on the association between prenatal and early postnatal exposure to environmental chemicals and the development of autism in epidemiological studies and rodent models of autism. METHODS: PubMed was searched through 8 February 2018. Included studies assessed exposure to environmental chemicals prior to 2 months of age in humans or 14 d in rodents. Rodent studies were considered relevant if they included at least one measurement of reciprocal social communicative behavior or repetitive and stereotyped behavior. Study details are presented in interactive displays using Tableau Public. RESULTS: The search returned 21,603 unique studies, of which 54 epidemiological studies, 46 experimental rodent studies, and 50 reviews were deemed relevant, covering 152 chemical exposures. The most frequently studied exposures in humans were particulate matter ([Formula: see text]), mercury ([Formula: see text]), nonspecific air pollution ([Formula: see text]), and lead ([Formula: see text]). In rodent studies, the most frequently studied exposures were chlorpyrifos ([Formula: see text]), mercury ([Formula: see text]), and lead ([Formula: see text]). DISCUSSION: Although research is growing rapidly, wide variability exists in study design and conduct, exposures investigated, and outcomes assessed. Conclusions focus on recommendations to guide development of best practices in epidemiology and toxicology, including greater harmonization across these fields of research to more quickly and efficiently identify chemicals of concern. In particular, we recommend chlorpyrifos, lead, and polychlorinated biphenyls (PCBs) be systematically reviewed in order to assess their relationship with the development of autism. There is a pressing need to move forward quickly and efficiently to understand environmental influences on autism in order to answer current regulatory questions and inform treatment and prevention efforts. https://doi.org/10.1289/EHP4386.

Exploring the endocrine activity of air pollutants associated with unconventional oil and gas extraction.

BACKGROUND: In the last decade unconventional oil and gas (UOG) extraction has rapidly proliferated throughout the United States (US) and the world. This occurred largely because of the development of directional drilling and hydraulic fracturing which allows access to fossil fuels from geologic formations that were previously not cost effective to pursue. This process is known to use greater than 1,000 chemicals such as solvents, surfactants, detergents, and biocides. In addition, a complex mixture of chemicals, including heavy metals, naturally-occurring radioactive chemicals, and organic compounds are released from the formations and can enter air and water. Compounds associated with UOG activity have been linked to adverse reproductive and developmental outcomes in humans and laboratory animal models, which is possibly due to the presence of endocrine active chemicals. METHODS: Using systematic methods, electronic searches of PubMed and Web of Science were conducted to identify studies that measured chemicals in air near sites of UOG activity. Records were screened by title and abstract, relevant articles then underwent full text review, and data were extracted from the studies. A list of chemicals detected near UOG sites was generated. Then, the potential endocrine activity of the most frequently detected chemicals was explored via searches of literature from PubMed. RESULTS: Evaluation of 48 studies that sampled air near sites of UOG activity identified 106 chemicals detected in two or more studies. Ethane, benzene and n-pentane were the top three most frequently detected. Twenty-one chemicals have been shown to have endocrine activity including estrogenic and androgenic activity and the ability to alter steroidogenesis. Literature also suggested that some of the air pollutants may affect reproduction, development, and neurophysiological function, all endpoints which can be modulated by hormones. These chemicals included aromatics (i.e., benzene, toluene, ethylbenzene, and xylene), several polycyclic aromatic hydrocarbons, and mercury. CONCLUSION: These results provide a basis for prioritizing future primary studies regarding the endocrine disrupting properties of UOG air pollutants, including exposure research in wildlife and humans. Further, we recommend systematic reviews of the health impacts of exposure to specific chemicals, and comprehensive environmental sampling of a broader array of chemicals.

Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) has increased in prevalence in the past decade. Studies attempting to identify a specific genetic component have not been able to account for much of the heritability of ADHD, indicating there may be gene-environment interactions underlying the disorder, including early exposure to environmental chemicals. Based on several relevant studies, we chose to examine bisphenol A (BPA) as a possible contributor to ADHD in humans. BPA is a widespread environmental chemical that has been shown to disrupt neurodevelopment in rodents and humans. OBJECTIVES: Using the Office of Health Assessment and Translation (OHAT) framework, a systematic review and meta-analysis was designed to determine the relationship between early life exposure to BPA and hyperactivity, a key diagnostic criterion of ADHD. DATA SOURCES: Searches of PubMed, Web of Science, and Toxline were completed for all literature to January 1, 2017. STUDY ELIGIBILITY CRITERIA: For inclusion, the studies had to publish original data, be in the English language, include a measure of BPA exposure, and assess if BPA exposure affected hyperactive behaviors in mice, rats or humans. Exposure to BPA had to occur at <3 months of age for humans, up to postnatal day 35 for rats and up to postnatal day 40 for mice. Exposure could occur either gestationally (via maternal exposure) or directly to the offspring. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were evaluated using the OHAT risk of bias tool. The effects in humans were assessed qualitatively. For rodents exposed to 20 µg/kg/day BPA, we evaluated the study findings in a random effects meta-analytical model. RESULTS: A review of the literature identified 29 rodent and 3 human studies. A random effects meta-analysis showed significantly increased hyperactivity in male rodents. In humans, early BPA exposure was associated with hyperactivity in boys and girls. LIMITATIONS, CONCLUSIONS, AND IMPLICATIONS OF KEY FINDINGS: We concluded that early life BPA exposure is a presumed human hazard for the development of hyperactivity. Possible limitations of this systematic review include deficiencies in author reporting, exclusion of some literature based on language, and insufficient similarity between human studies. SRs that result in hazard-based conclusions are the first step in assessing and mitigating risks. Given the widespread exposure of BPA and increasing diagnoses of ADHD, we recommend immediate actions to complete such risk analyses and take next steps for the protection of human health. In the meantime, precautionary measures should be taken to reduce exposure in pregnant women, infants and children. The present analysis also discusses potential mechanisms by which BPA affects hyperactivity, and the most effective avenues for future research. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not available.

The occurrence of intersex fishes in Boulder Creek, Colorado, is a recent phenomenon.

Gonads were examined visually and histologically from white sucker (Catostomus commersoni) and fathead minnows (Pimephales promelas) isolated from museum specimens collected from Boulder Creek, Colorado. These fishes were collected between 42 and 102 years ago before addition of large quantities of estrogenic chemicals via wastewater effluent was reported to disrupt reproductive structures and functions in white suckers living in Boulder Creek downstream of the wastewater treatment facility (WWTF) and in test exposures of fathead minnows to wastewater effluent at the WWTF. No evidence of abnormal external gonad appearance or histology (e.g., testicular oocytes, mixed gonadal tissue) were observed in male or female museum specimens of either species supporting the conclusion that observations of reproductive abnormalities, feminization, demasculinization, and altered sex ratios are recent phenomena.

Melamine, beyond the kidney: A ubiquitous endocrine disruptor and neurotoxicant?

Melamine is commonly used in a variety of consumer products such as furniture, dining ware, and food utensils. The chemical infamously gained worldwide attention by its illegal addition to a variety of foodstuffs in order to falsify protein content, which led to serious, sometimes fatal, health impacts in children and pets. This resulted in a large amount of published primary studies and reviews of the impacts of melamine exposure on kidney function. However, a growing body of literature suggests that melamine may have impacts beyond renal dysfunction. We conducted a scoping review of this literature which yielded more than 40 studies with human, animal, and in vitro findings. Neurological impacts, reproductive function, and anthropometric outcomes were identified as possible candidates for systematic review based on evidence stream and replication of endpoints. The results of this analysis provide a basis for prioritizing future research on health impacts associated with melamine exposure.

Polycyclic aromatic hydrocarbons and female reproductive health: A scoping review.

Polycyclic aromatic hydrocarbons (PAHs) are a class of common persistent environmental pollutants found in water, air, soil, and plants and can be released by natural sources. However, the majority of atmospheric PAHs are from vehicular emissions, coal-burning plants, and the production and use of petroleum-derived substances. Exposure to PAHs has been implicated in cancer and other diseases, including reproductive disorders. This scoping review is a preliminary step that explores the utility and feasibility of completing a systematic review evaluating the effect of PAHs on female reproduction. We performed literature searches in PubMed, Web of Science, and Scopus, then screened, identified, and categorized relevant studies. Our results identified fertility and pregnancy/fetal viability as outcomes with sufficient research for systematic review. In addition to presenting the relevant studies, the review identifies data gaps, and provides the groundwork to develop the most appropriate research questions for systematic review.

Potential Developmental and Reproductive Impacts of Triclocarban: A Scoping Review.

Triclocarban (TCC) is an antimicrobial agent used in personal care products. Although frequently studied with another antimicrobial, triclosan, it is not as well researched, and there are very few reviews of the biological activity of TCC. TCC has been shown to be a possible endocrine disruptor, acting by enhancing the activity of endogenous hormones. TCC has been banned in the US for certain applications; however, many human populations, in and outside the US, exhibit exposure to TCC. Because of the concern of the health effects of TCC, we conducted a scoping review in order to map the current body of literature on the endocrine, reproductive, and developmental effects of TCC. The aim of this scoping review was to identify possible endpoints for future systematic review and to make recommendations for future research. A search of the literature until August 2017 yielded 32 relevant studies in humans, rodents, fish, invertebrates, and in vitro. Based on the robustness of the literature in all three evidence streams (human, animal, and in vitro), we identified three endpoints for possible systematic review: estrogenic activity, androgenic activity, and offspring growth. In this review, we describe the body of evidence and make recommendations for future research.

New Look at BTEX: Are Ambient Levels a Problem?

Benzene, toluene, ethylbenzene, and xylene (BTEX) are retrieved during fossil fuel extraction and used as solvents in consumer and industrial products, as gasoline additives, and as intermediates in the synthesis of organic compounds for many consumer products. Emissions from the combustion of gasoline and diesel fuels are the largest contributors to atmospheric BTEX concentrations. However, levels indoors (where people spend greater than 83% of their time) can be many times greater than outdoors. In this review we identified epidemiological studies assessing the noncancer health impacts of ambient level BTEX exposure (i.e., nonoccupational) and discussed how the health conditions may be hormonally mediated. Health effects significantly associated with ambient level exposure included sperm abnormalities, reduced fetal growth, cardiovascular disease, respiratory dysfunction, asthma, sensitization to common antigens, and more. Several hormones including estrogens, androgens, glucocorticoids, insulin, and serotonin may be involved in these health outcomes. This analysis suggests that all four chemicals may have endocrine disrupting properties at exposure levels below reference concentrations (i.e., safe levels) issued by the U.S. Environmental Protection Agency. These data should be considered when evaluating the use of BTEX in consumer and industrial products and indicates a need to change how chemicals present at low concentrations are assessed and regulated.

Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes.

BACKGROUND: Increasing concern over bisphenol A (BPA) as an endocrine-disrupting chemical and its possible effects on human health have prompted the removal of BPA from consumer products, often labeled "BPA-free." Some of the chemical replacements, however, are also bisphenols and may have similar physiological effects in organisms. Bisphenol S (BPS) and bisphenol F (BPF) are two such BPA substitutes. OBJECTIVES: This review was carried out to evaluate the physiological effects and endocrine activities of the BPA substitutes BPS and BPF. Further, we compared the hormonal potency of BPS and BPF to that of BPA. METHODS: We conducted a systematic review based on the Office of Health Assessment and Translation (OHAT) protocol. RESULTS: We identified the body of literature to date, consisting of 32 studies (25 in vitro only, and 7 in vivo). The majority of these studies examined the hormonal activities of BPS and BPF and found their potency to be in the same order of magnitude and of similar action as BPA (estrogenic, antiestrogenic, androgenic, and antiandrogenic) in vitro and in vivo. BPS also has potencies similar to that of estradiol in membrane-mediated pathways, which are important for cellular actions such as proliferation, differentiation, and death. BPS and BPF also showed other effects in vitro and in vivo, such as altered organ weights, reproductive end points, and enzyme expression. CONCLUSIONS: Based on the current literature, BPS and BPF are as hormonally active as BPA, and they have endocrine-disrupting effects. CITATION: Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes.

Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.

Challenging the role of adaptive immunity in neurotrauma: Rag1(-/-) mice lacking mature B and T cells do not show neuroprotection after closed head injury.

The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1(-/-) mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1(-/-) mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood-brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1(-/-) mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1(-/-) mice compared to wild-type animals. In contrast, the levels of pro- and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1(-/-) compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1(-/-) mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.