The Epigenetic and Neurodevelopmental Consequences of Maternal Tobacco Smoke Exposure

Maternal smoking is a deleterious and preventable risk to fetal health. Maternal tobacco smoke (TS) exposure in humans has been linked to impaired fetal growth, preterm birth, sudden infant death syndrome, and neurobehavioral disorders including cognitive dysfunction, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In the United States, nearly 10% of pregnant women smoke despite ongoing public health efforts to reduce the incidence of smoking. Of additional concern is the steady rise of electronic nicotine delivery systems (ENDS) use among pregnant women over the past decade. Further, ENDS are often used in conjunction with tobacco cigarettes, compounding exposure effects. In animal models, both maternal TS and nicotine exposure lead to adverse neurodevelopmental outcomes, including increased anxiety and ADHD-like behavior, that are transmitted to subsequent generations. A likely explanation for this phenomenon lies in early developmental epigenetic programming. Epigenetic markers that are established early in development, like DNA methylation, can persist throughout somatic cell division and gametogenesis. During early development, zygotic DNA methylation is reprogrammed following a wave of global demethylation, and only re-established during the peri-implantation period. Environmental perturbations during these critical phases of reprogramming have been associated with persistent, and even transgenerationally-inherited effects, underscoring the importance of examining these associations in the context of human health and disease.The broader goals of this dissertation were to identify alterations in DNA methylation patterning in the brain as a result of maternal TS exposure, and assess their neurodevelopmental significance. In an effort to better understand the effects of nicotine alone, especially given the increasing usage of ENDS during pregnancy, we chose to examine developmental nicotine exposure in addition to TS exposure. Finally, we evaluated the translational significance of these alterations by examining correlations in humans developmentally exposed to TS. Using a rat model for gestational nicotine exposure, DNA methylation levels were measured in the brains of neonatal and adult rats to determine the persistence of exposure effects. Specific brain regions, including the rat preoptic area (POA), hippocampus and cortex were targeted for evaluation based on their neurobehavioral significance. A rat gestational exposure model for tobacco smoke extract (TSE) was further employed to determine potential overlap with methylomic regions affected by developmental nicotine exposure. Finally, to derive translational implications, DNA methylation was examined on both epigenome-wide and targeted levels in human cord blood from newborns exposed to maternal TS.In neonatal rats developmentally exposed to nicotine, DNA methylation was reduced in regions implicated in masculinization of the preoptic area (POA), a region of the brain that requires epigenetic reprogramming events to sexually differentiate. Subsequent behavioral analyses in adulthood revealed that these alterations may have contributed to the developmental masculinization of the POA in nicotine-exposed females. In adults males developmentally exposed to nicotine, alterations to DNA methylation were observed in the hippocampus and cortex, two brain regions that are also associated with ADHD- and ASD-like behaviors, respectively. Further, a comparison of differentially-methylated regions (DMRs) between the brains of animals exposed to developmental nicotine and TSE revealed significant overlap, indicating that nicotine is largely driving the developmental alterations to DNA methylation observed in TSE-exposed animals. Examination of DNA methylation alterations in human infant cord blood as a result of maternal TS exposure indicated significant overlap with those revealed in rats, supporting common impacts on developmental epigenetic reprogramming across species. Moreover, nearly half of these common regions were implicated in neurodevelopmental disorders, namely ASD and ADHD. Alterations to DNA methylation at human metastable epialleles, or regions for which DNA methylation is stochastically established during early development, were observed in the cord blood of infants exposed to TS in utero, supporting the ability of TS-exposure to alter vulnerable regions of the epigenome during early developmental reprogramming.</p

Usage of Children&rsquo;s Makeup and Body Products in the United States and Implications for Childhood Environmental Exposures

There is growing evidence of toxicity associated with ingredients found in cosmetics and personal care products. Children&rsquo;s makeup and body products (CMBPs) are widely marketed to children throughout the US; however, little is known about how and why children use them. We administered a survey to parents/guardians of children aged &le;12 years about the use of CMBPs. Among all the children (n = 312) of survey respondents (n = 207), 219 (70%) have used CMBPs in their lifetime. Older children used CMBPs at higher rates than younger children, and female children used CMBPs at higher rates than male children. Children of Hispanic/Latinx parents/guardians used CMBPs more often and for shorter durations and a greater proportion used lip, hair, and fragrance products than children of non-Hispanic parents/guardians. Approximately half the children that use CMBPs were reported to use them with play intentions. Compared to children of non-Hispanic parents/guardians, children of Hispanic/Latinx parents/guardians reported more play motivations for CMBP use. Using qualitative analysis approaches, responses suggest CMBPs are commonly used for fun or play activities. This mixed methods analysis serves as an introduction to understanding early life exposures to this unique and understudied class of products

Overview of Reviews of the impact of non-chemical stressors on chemical exposures and adverse health outcomes

Background: Human health risk assessment that evaluate single stressor or exposure in relation to adverse health outcomes do not reflect real-life exposure or risk scenarios. Humans are exposed to multiple chemicals and non-chemical stressors at once. Additionally, existing risk assessment methods lack clear guidance on defining and characterizing the impact of non-chemical stressors. Objective: To identify and evaluate systematic reviews that assess the relationship between chemical exposure and adverse health outcomes and the additional influence of extrinsic non-chemical stressors on that relationship. Search and study eligibility: We will perform electronic searches in PubMed, web of science, Cochrane CENTRAL, Cochrane Reviews and MEDNAR. Reviews are eligible if they meet our PECO statement and additional eligibility criteria. Depending on the number and quality of the systematic reviews we identify, we may choose to refine our search strategy and study selection criteria to include primary studies to update an existing systematic or scoping review. Study appraisal, data analysis and synthesis: Eligible reviews will be assessed using a modified version of the AMSTAR 2.0 tool. We will extract and present results as reported by the review authors. We will produce summary statistics and may reanalyze the data if necessary. Conclusion: Findings from this overview will support additional research and policy efforts reducing health disparities due to extrinsic non-chemical stressors for chemical exposures

Aqueous spice extracts as alternative antimycotics to control highly drug resistant extensive biofilm forming clinical isolates of Candida albicans.

Candida albicans form biofilm by associating with biotic and abiotic surfaces. Biofilm formation by C. albicans is relevant and significant as the organisms residing within, gain resistance to conventional antimycotics and are therefore difficult to treat. This study targeted the potential of spice-based antimycotics to control C. albicans biofilms. Ten clinical isolates of C. albicans along with a standard culture MTCC-3017 (ATCC-90028) were screened for their biofilm-forming ability. C. albicans M-207 and C. albicans S-470 were identified as high biofilm formers by point inoculation on Trypticase Soy Agar (TSA) medium as they formed a lawn within 16 h and exhibited resistance to fluconazole and caspofungin at 25 mcg and 8 mcg respectively. Aqueous and organic spice extracts were screened for their antimycotic activity against C. albicans M-207 and S-470 by agar and disc diffusion and a Zone of Inhibition was observed. Minimal Inhibitory Concentration was determined based on growth absorbance and cell viability measurements. The whole aqueous extract of garlic inhibited biofilms of C. albicans M-207, whereas whole aqueous extracts of garlic, clove, and Indian gooseberry were effective in controlling C. albicans S-470 biofilm within 12 h of incubation. The presence of allicin, ellagic acid, and gallic acid as dominant compounds in the aqueous extracts of garlic, clove, and Indian gooseberry respectively was determined by High-Performance Thin Layer Chromatography and Liquid Chromatography-Mass Spectrometry. The morphology of C. albicans biofilm at different growth periods was also determined through bright field microscopy, phase contrast microscopy, and fluorescence microscopy. The results of this study indicated that the alternate approach in controlling high biofilm-forming, multi-drug resistant clinical isolates of C. albicans M-207 and S-470 using whole aqueous extracts of garlic, clove, and Indian gooseberry is a safe, potential, and cost-effective one that can benefit the health care needs with additional effective therapeutics to treat biofilm infections

Developmental nicotine exposure and masculinization of the rat preoptic area.

Nicotine is a neuroteratogenic component of tobacco smoke, e-cigarettes, and other products and can exert sex-specific effects in the developing brain, likely mediated through sex hormones. Estradiol modulates expression of nicotinic acetylcholine receptors in rats, and plays critical roles in neurodevelopmental processes, including sexual differentiation of the brain. Here, we examined the effects of developmental nicotine exposure on the sexual differentiation of the preoptic area (POA), a brain region that normally displays robust structural sexual dimorphisms and controls adult mating behavior in rodents. Using a rat model of gestational exposure, developing pups were exposed to nicotine (2 mg/kg/day) via maternal osmotic minipump (subcutaneously, sc) throughout the critical window for brain sexual differentiation. At postnatal day (PND) 4, a subset of offspring was analyzed for epigenetic effects in the POA. At PND40, all offspring were gonadectomized, implanted with a testosterone-releasing capsule (sc), and assessed for male sexual behavior at PND60. Following sexual behavior assessment, the area of the sexually dimorphic nucleus of the POA (SDN-POA) was measured using immunofluorescent staining techniques. In adults, normal sex differences in male sexual behavior and in the SDN-POA area were eliminated in nicotine-treated animals. Using novel analytical approaches to evaluate overall masculinization of the adult POA, we identified significant masculinization of the nicotine-treated female POA. In neonates (PND4), nicotine exposure induced trending alterations in methylation-dependent masculinizing gene expression and DNA methylation levels at sexually-dimorphic differentially methylated regions, suggesting that developmental nicotine exposure is capable of triggering masculinization of the rat POA via epigenetic mechanisms

Addressing systemic problems with exposure assessments to protect the public’s health

Abstract Background Understanding, characterizing, and quantifying human exposures to environmental chemicals is critical to protect public health. Exposure assessments are key to determining risks to the general population and for specific subpopulations given that exposures differ between groups. Exposure data are also important for understanding where interventions, including public policies, should be targeted and the extent to which interventions have been successful. In this review, we aim to show how inadequacies in exposure assessments conducted by polluting industries or regulatory agencies have led to downplaying or disregarding exposure concerns raised by communities; that underestimates of exposure can lead regulatory agencies to conclude that unacceptable risks are, instead, acceptable, allowing pollutants to go unregulated; and that researchers, risk assessors, and policy makers need to better understand the issues that have affected exposure assessments and how appropriate use of exposure data can contribute to health-protective decisions. Methods We describe current approaches used by regulatory agencies to estimate human exposures to environmental chemicals, including approaches to address limitations in exposure data. We then illustrate how some exposure assessments have been used to reach flawed conclusions about environmental chemicals and make recommendations for improvements. Results Exposure data are important for communities, public health advocates, scientists, policy makers, and other groups to understand the extent of environmental exposures in diverse populations. We identify four areas where exposure assessments need to be improved due to systemic sources of error or uncertainty in exposure assessments and illustrate these areas with examples. These include: (1) an inability of regulatory agencies to keep pace with the increasing number of chemicals registered for use or assess their exposures, as well as complications added by use of ‘confidential business information’ which reduce available exposure data; (2) the failure to keep assessments up-to-date; (3) how inadequate assumptions about human behaviors and co-exposures contribute to underestimates of exposure; and (4) that insufficient models of toxicokinetics similarly affect exposure estimates. Conclusion We identified key issues that impact capacity to conduct scientifically robust exposure assessments. These issues must be addressed with scientific or policy approaches to improve estimates of exposure and protect public health

Time for CHANGE : System-level interventions for bringing forward the date of effective use of NAMs in regulatory toxicology

There has been considerable work over the past 20 years designed to bring about a paradigm shift in regulatory toxicology from chemical risk management decisions based on data from animal studies to a “Next Generation Risk Assessments” (NGRAs) system founded on New Approach Methods (NAMs). The perceived potential benefits of NAMs that are driving the paradigm shift include better protection of humans and the environment, the reduction of animal testing, and ultimately, a faster and more cost-effective test systems for evaluating chemical safety. In this article, we introduce the “Collaboration to Harmonise the Assessment of Next Generation Evidence” (CHANGE) project, a new initiative that seeks to design system-level interventions for bringing forward the date of effective use of NAMs, explaining its goals, approach, project management, governance, and funding