Effects Of Early-life Exposure Research Articles

Effects of Early Life Exposure to Sex Hormones on Neurochemical and Behavioral Responses to Psychostimulants in Adulthood: Implications in Drug Addiction.

Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.

The Effect of Early Life Exposure to Triclosan on Thyroid Follicles and Hormone Levels in Zebrafish.

Triclosan (TCS) is an antimicrobial chemical widely used in personal care products. Most of the TCS component is discharged and enters the aquatic ecosystem after usage. TCS has a similar structure as thyroid hormones that are synthesized by thyroid follicular epithelial cells, thus TCS has a potential endocrine disrupting effect. It is still not clear how the different levels of the environmental TCS would affect early development in vivo. This study examines the effects of TCS on thyroid hormone secretion and the early development of zebrafish. The fertilized zebrafish eggs were exposed to TCS at 0 (control), 3, 30, 100, 300, and 900 ng/mL, and the hatching rate and the larvae mortality were inspected within the first 14 days. The total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) were measured at 7, 14, and 120 days post-fertilization (dpf). The histopathological examinations of thyroid follicles were conducted at 120 dpf. TCS exposure at 30-300 ng/mL reduced the hatching rate of larvae to 34.5% to 28.2 % in the first 48 hours and 93.8 .7 % to 86.8 % at 72 h. Extremely high TCS exposure (900 ng/mL) strongly inhibited the hatching rate, and all the larvae died within 1 day. Exposure to TCS from 3 to 300 ng/mL reduced the thyroid hormones production. The mean TT3 and FT3 levels of zebrafish decreased in 300 ng/mL TCS at 14 dpf (300 ng/mL TCS vs. control : TT3 , 0.19 ± 0.08 vs. 0.39 ± 0.06; FT3, 19.21 ± 3.13 vs. 28.53 ± 1.98 pg/mg), and the FT4 decreased at 120 dpf ( 0.09 ± 0.04 vs. 0.20 ± 0.14 pg/mg). At 120 dpf , in the 300 ng/mL TCS exposure group, the nuclear area and the height of thyroid follicular epithelial cells became greater, and the follicle cell layer got thicker. This happened along with follicle hyperplasia, nuclear hypertrophy, and angiogenesis in the thyroid. Our study demonstrated that early life exposure to high TCS levels reduces the rate and speed of embryos hatching, and induces the histopathological change of thyroid follicle, and decreases the TT3, FT3, and FT4 production in zebrafish.

Environmental contaminants and child development: Developmentally-informed opportunities and recommendations for integrating and informing child environmental health science.

Child environmental health (CEH) science has identified numerous effects of early life exposures to common, ubiquitous environmental toxicants. CEH scientists have documented the costs not only to individual children but also to population-level health effects of such exposures. Importantly, such risks are unequally distributed in the population, with historically marginalized communities and the children living in these communities receiving the most damaging exposures. Developmental science offers a lens and set of methodologies to identify nuanced biological and behavioral processes that drive child development across physical, cognitive, and socioemotional domains. Developmental scientists are also experts in considering the multiple, hierarchically-layered contexts that shape development alongside toxicant exposure. Such contexts and the individuals acting within them make up an overarching "child serving ecosystem" spanning systems and sectors that serve children directly and indirectly. Articulating how biobehavioral mechanisms and social-ecological contexts unfold from a developmental perspective are needed in order to inform CEH translation and intervention efforts across this child-serving ecosystem. Developmentalists can also benefit from integrating CEH science findings in their work by considering the role of the physical environment, and environmental toxicants specifically, on child health and development. Building on themes that were laid out by Trentacosta and Mulligan in 2020, this commentary presents recommendations for connecting developmental and CEH science and for translating such work so that it can be used to promote child development in an equitable manner across this child-serving ecosystem. These opportunities include (1) Using Developmentally-Informed Conceptual Models; (2) Applying Creative, Sophisticated, and Rigorous Methods; (3) Integrating Developmentally-Sensitive Intervention Considerations; and (4) Establishing Interdisciplinary Collaborations and Cross-Sector Partnerships.

Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner

BackgroundNanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague–Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2–5, PND 7–10, or PND 17–20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses.ResultsHeart rate was found to be significantly decreased in female pups when dosed between PND 7–10 and PND 17–20. Females dosed between PND 2–5 showed decrease acoustic startle response and when dosed between PND 7–10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17–20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism.ConclusionOral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

PSVI-24 Effects of early-life exposure to topsoil on the muscle fiber characteristics and gene expression of weaned piglets

Abstract The objective of this experiment was to investigate the influence of early exposure to topsoil on the muscle fiber characteristics and transcription-related myogenesis, intramuscular fat metabolism, muscle fiber types, and mTOR signaling pathway of weaned pigs. A Total of 180 piglets were separately assigned to the No soil, Antibacterial soil, and Normal soil group (each group, n = 60), and were fed ad libitum with common antibiotic-free corn-soybean meal diets until day-31. Ten pigs from each group with similar body weight were selected to be slaughtered, and the Longissimus dorsi (LD) muscle samples were collected for histological analysis and measurements of genes and protein expression levels. In the present study, the muscle fiber diameter and the area of the Normal soil and Antibacterial soil group were significantly higher than the No soil group (P < 0.05). The Normal soil significantly upregulated the gene expression of MyoG compared to No soil and Antibacterial soil groups (P < 0.05). The gene expression of CD36 and CPT-1 of the Normal soil group was significantly lower than the No soil group (P < 0.05), while HSL expression of the Normal soil group was significantly higher than the Antibacterial and No soil groups (P < 0.05). The MyHC I of the Normal soil group was significantly higher than the No soil group (P < 0.05), but the expression MyHC IIa was lower than the No soil group (P < 0.05). The protein expression expressed a similar result with gene expression. In addition, the Normal soil significantly increased the AMPK and mTOR phosphorylation compared to No soil and Antibacterial soil groups (P < 0.05). These data suggest that early exposure to topsoil regulates muscle fiber growth, modulates the expression pattern related to myogenesis, muscle fiber type, intramuscular fat metabolism, and increases the phosphorylation of mTOR and AMPK pathways.

Short- and long-term effects of early life exposure to concentrate or hay on feed sorting and rumen fermentation

Feed sorting is a common issue on dairy farms. Cows prefer smaller grain particles over long forage particles, leading to increased volatile fatty acids (VFA) and consequently subacute ruminal acidosis (SARA). The purpose of this study was to investigate the short and long-term effects of early life exposure to different feed sources on feed sorting and rumen fermentation of calves. Forty newborn female Holstein calves were randomly assigned at birth (38.5 ± 2.4 kg of BW) to 1 of 2 treatments: (1) the provision of concentrate (CON) only or (2) provision of hay (HAY) only as the source of solid feed during the milk-feeding stage (d 1–56). Afterward, all calves were offered a total mixed ration until the end of the experiment (d 57–196). Calves were raised in individual hutches from d 1–70. The calves were then transferred into a heifer barn with pens and housed in pairs (2 calves/pen) as per the previous treatments. Rectal temperature, feed intake, body weight and body structural measurements were recorded throughout the study. Fresh feed and orts were sampled daily in the first two weeks (d 57–70) of feeding TMR and in the last week of the experiment (d 190–196) to analyze feed sorting behaviour. Rumen fluid samples were collected from d 14–190 for detecting VFA concentrations. Our findings showed that early feed exposure did not influence calf health and growth performance but affected feed sorting over a short period. Upon transition to the same mixed diet, differences were found in the sorting of different particle fractions between treatments. In the first two weeks (wk 9 and 10) after transition to TMR, calves exposed to concentrates early began to sort for fine particle and against the long particle fractions. In contrast, calves fed hay early sorted for the long particle and against the fine particle fractions, resulting in a higher preference for fine particle fractions (P < 0.01) and a lower preference for long particle fractions (P < 0.01) in calves fed concentrate early than those fed hay early. However, no carryover effects were observed, such that differences between treatments in sorting for long (P = 0.43) and fine (P = 0.45) particle fractions faded away by the last week (wk 28) of the experiment. All calves sorted for short and fine particle fractions and against long and medium particle fractions. Although the pattern of feed sorting initially differed between treatments, rumen fermentation parameters, such as total VFA (P = 0.54), acetate (P = 0.83), propionate (P = 0.21), butyrate (P = 0.20), were not altered once all calves transitioned to a total mixed ration. These results suggested that the feed familiarity established early in life would not affect diet selection and rumen fermentation in heifer later in life. Moreover, the effect of feeding a total mixed ration after transition could eventually override the effect of feeding concentrate or hay early in life.

Context‐dependent carryover effects of hypoxia and warming in a coastal ecosystem engineer

Organisms are increasingly likely to be exposed to multiple stressors repeatedly across ontogeny as climate change and other anthropogenic stressors intensify. Early life stages can be particularly sensitive to environmental stress, such that experiences early in life can “carry over” to have long‐term effects on organism fitness. Despite the potential importance of these within‐generation carryover effects, we have little understanding of how they vary across ecological contexts, particularly when organisms are re‐exposed to the same stressors later in life. In coastal marine systems, anthropogenic nutrients and warming water temperatures are reducing average dissolved oxygen (DO) concentrations while also increasing the severity of naturally occurring daily fluctuations in DO. Combined effects of warming and diel‐cycling DO can strongly affect the fitness and survival of coastal organisms, including the eastern oyster (Crassostrea virginica), a critical ecosystem engineer and fishery species. However, whether early life exposure to hypoxia and warming affects oysters' subsequent response to these stressors is unknown. Using a multiphase laboratory experiment, we explored how early life exposure to diel‐cycling hypoxia and warming affected oyster growth when oysters were exposed to these same stressors 8 weeks later. We found strong, interactive effects of early life exposure to diel‐cycling hypoxia and warming on oyster tissue : shell growth, and these effects were context‐dependent, only manifesting when oysters were exposed to these stressors again two months later. This change in energy allocation based on early life stress exposure may have important impacts on oyster fitness. Exposure to hypoxia and warming also influenced oyster tissue and shell growth, but only later in life. Our results show that organisms' responses to current stress can be strongly shaped by their previous stress exposure, and that context‐dependent carryover effects may influence the fitness, production, and restoration of species of management concern, particularly for sessile species such as oysters.

Epigenetic changes by per- and polyfluoroalkyl substances (PFAS).

Increasing studies are examining per- and polyfluoroalkyl substances (PFAS) induced toxicity and resulting health outcomes, including epigenetic modifications (e.g., DNA methylation, histone modification, microRNA expression). We critically reviewed current evidence from human epidemiological, invitro, and animal studies, including mammalian and aquatic model organisms. Epidemiological studies identified the associations between perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) exposure and epigenetic changes in both adult populations and birth cohorts. For invitro studies, various cell types including neuroblasts, preadipocytes, and hepatocytes have been employed to understand epigenetic effects of PFAS. In studies with animal models, effects of early life exposure to PFAS have been examined using rodent models, and aquatic models (e.g., zebrafish) have been more frequently used in recent years. Several studies highlighted oxidative stress as a key mediator between epigenetic modification and health effects. Collectively, previous research clearly suggest involvement of epigenetic mechanisms in PFAS induced toxicity, though these efforts have primarily focused on specific PFASs (i.e. mainly PFOS and PFOA) or endpoints (i.e. cancer). Additional studies are necessary to define specific linkages among epigenetic mechanisms and related biomarkers or phenotypical changes. In addition, future research is also needed for understudied PFAS and complex mixtures. Studies of epigenetic effects elicited by individual PFAS and mixtures are needed within an adverse outcome pathways framework, which will advance an understanding of PFAS risks to public health and the environment, and support efforts to design less hazardous chemicals.

The Long-term Effects of Violent Conflict on Women’s Intra-Household Decision-Making Power

Does exposure to civil war during childhood affect women’s later-life intra-household decision-making power? This paper examines the long-term effects of early-life exposure to the Nigerian Civil War on women’s decision-making power within the household, using data from the 2008 Nigerian Demographic and Health Survey. To identify the effects, we adopt a difference-in-differences approach which exploits variation in exposure to the civil war by year of birth and ethnicity. The results show that early-life exposure to the war decreases the likelihood of women’s decision-making power within the household in adulthood. Likely mechanisms include different fertility and marriage choices as well as poorer education, health, and employment outcomes as a result of exposure to the war, which would place women in a more precarious position in the household relative to their partners.

Heart development in two populations of Atlantic killifish (Fundulus heteroclitus) following exposure to a polycyclic aromatic hydrocarbon mixture

Historic industrial pollution of the Elizabeth River, Virginia resulted in polycyclic aromatic hydrocarbon (PAH) contamination in sediments. Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood (AW) industrial site adapted to complex PAH mixture at this Superfund site. Their embryos have proved highly resistant to cardiac abnormalities indicative of PAH toxicity. In this study, embryos spawned from adults collected at AW and King’s Creek (KC), a reference site, were exposed at 24 h post fertilization (hpf) to Elizabeth River Sediment Extract (ERSE), a complex PAH mixture, in a range of concentrations (0, 5.04, 50.45, 100.90, 151.35, or 252.25 µg/L total PAHs). Embryos were processed for histology at 144 hpf to enable evaluations of hearts at tissue and cellular levels. Morphometry and severity scoring were used to evaluate the extent of alterations. Unexposed embryos were similar in both populations. ERSE exposure resulted in multiple changes to hearts of KC embryos but not AW. Alterations were particularly evident in KC embryos exposed to concentrations above 1% ERSE (50.45 µg/L), which had thinner ventricular walls and larger pericardial edema. Individuals with moderate pericardial edema maintained arrangement and proximity of heart chambers, but changes were seen in ventricular myocytes. Severe pericardial edema was prevalent in exposed KC embryos and typically resulted in tube heart formation. Ventricles of tube hearts had very thin walls composed of small, basophilic cells and lacked trabeculae. Edematous pericardial fluid contained small amounts of proteinaceous material, as did controls, and was free of cells. This fluid was primarily unstained, suggesting water influx due to increased permeability. The use of histological approaches provided more specific detail for tissue and cellular effects in hearts of embryos exposed to PAHs and enabled understanding of potential links to later life effects of early life exposure.

Early life exposure to fine particulate matter and childhood asthma in Beijing, China: A case-control study

Background: Previous studies indicated that the effect of early life exposure to ambient air pollution on childhood asthma is still unclear. Methods: A case-control study for children in 2010 was performed in Beijing. A spatio-temporal model was developed using PM2.5 (particles with an aerodynamic diameter of less than 2.5 μm) data from 35 monitoring stations and the geographic information data from 2013, which was time-adjusted and then be applied to estimate the personal exposure level in 2004-2010. Logistic regression model was used to examine the effects of PM2.5 exposure during different pre-natal (the first trimester, second trimester, third trimester and whole pregnancy) and post-natal periods (the first year after birth) on childhood asthma.Results: In total, 118 cases (mean:4.5 ys) and 133 healthy controls (mean:4.3 ys) were included in this study. The PM2.5 exposure level of asthma cases ranged from 74.4 to 233.0 μg /m3 in different time windows of early life. The level of PM2.5 in the case group was higher than that in the control group (P&lt;0.05). The exposure to PM2.5 during the whole pregnancy had an effect on asthma in the preschool children, with OR of 1.77 (95% CI: 1.33-2.36) for per 10 μg/m3 increase in PM2.5. The sensitive exposure window during pregnancy was the second trimester, with OR of 1.25 (95% CI: 1.10-1.41) for per 10 μg/m3 increase in PM2.5. PM2.5 exposure in the first year after birth also had an effect on asthma in the preschool children, with OR of 1.34 (95% CI: 1.07-1.68), and the risk was higher than that in the sensitive window of pregnancy. Conclusions: Exposures to PM2.5 during pregnancy and the first year of life were associated with the increased risk of asthma and there appeared to be stronger effects on asthma in the second trimester and the first year after birth.

Consequences of early life exposure to the 1983-1985 Ethiopian Great Famine on cognitive function in adults: a historical cohort study.

ObjectivesTo investigate the association between early life famine exposure and cognitive function in adults.DesignHistorical cohort studySettingNorth Wollo Zone, Northeast Ethiopia.ParticipantsWe recruited 1047 adult men and women aged 30–38 years who had history of early life exposure to Ethiopian great famine. Based on self-reported age and birth date, participants were categorised into famine exposed in early life (prenatal/postnatal) and non-exposed groups.Outcome measuresThe primary outcome measure of this study was cognitive function in adults after early life exposure to famine. Cognitive function was measured using Montreal Cognitive Assessment—basic. Associations between exposure and outcome variables were examined by linear regression analysis models.ResultsAdjusted for covariates, early life exposure to famine showed 1.29 (β=−1.29; 95% CI −2.16 to -0.52) points lower cognitive function score compared with non-exposed. Based on subanalysis for timing of famine exposure, postnatal exposure to famine resulted in 2.26 (β=−2.26; 95% CI −3.12 to -1.36) points lower cognitive function score compared with non-exposed groups. Prenatal famine exposure had 1.26 (β=−1.26; 95% CI −2.35 to 0.94) points lower cognitive function score although not statistically significant.ConclusionsFamine exposure in early life was associated with cognitive functions in adults. While the overall findings highlight the importance of optimal nutrition in early life for brain growth and development, the association observed between postnatal famine exposure and adult cognitive function may indicate the relative importance of learning and experience during early childhood for optimal brain development after birth. Further studies are needed to elucidate the potential mechanism behind this association.

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children

BackgroundThe adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows.MethodsWe investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites.ResultsMaternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure.ConclusionIn this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.

Early life factors are associated with risk for eosinophilic esophagitis diagnosed in adulthood.

Early life exposures have been associated with pediatric eosinophilic esophagitis (EoE), but it is unknown if a similar association is present in adults. We aimed to assess the association between early life risk factors and development of EoE in adulthood. To do this, we conducted a case-control study which was nested within a prospective cohort study of adults undergoing outpatient endoscopy. Cases of EoE were diagnosed per consensus guidelines; controls did not meet these criteria. Subjects and their mothers were contacted to collect information on four key early life exposures: antibiotics taken during the first year of life, Cesarean delivery, preterm delivery (≤37weeks' gestation), and neonatal intensive care unit (NICU) admission. We calculated the odds of EoE given in each exposure and assessed agreement between subjects and their mothers. For the 40 cases and 40 controls enrolled, we observed a positive association between each of the early life exposures and development of EoE (antibiotics in infancy, OR = 4.64, 95% CI = 1.63-13.2; Cesarean delivery, OR = 3.08, 95% CI = 0.75-12.6; preterm delivery, OR = 2.92, 95% CI = 0.71-12.0; NICU admission, OR = 4.00, 95% CI = 1.01-15.9). Results were unchanged after adjusting for potential confounders, though only early antibiotic use had CIs that did not cross 1.0. Moderate to strong agreement was observed between 54 subject-mother pairs (antibiotics, K = 0.44, P = 0.02; Cesarean delivery, K = 1.0, P < 0.001; preterm delivery, K = 0.80, P < 0.001; NICU, K = 0.76, P < 0.001). In sum, antibiotics in infancy was significantly associated with increased risk of EoE diagnosed in adulthood, while positive trends were seen with other early life factors such as Cesarean delivery, preterm delivery, and NICU admission. This may indicate persistent effects of early life exposures and merits additional study into conserved pathogenic mechanisms.

Early life exposure and its association with diseases in adulthood: review of longitudinal studies.

We describe the evidence of the effects of early life exposures on health and aging during adulthood. A narrative review of cohorts and systematic reviews of studies initiated early in life and followed up to adulthood was conducted. Most studies were carried out in developed countries. The long-term effects of birth weight and, to a lesser extent, height at birth on chronic-degenerative diseases, functionality, bone, renal and respiratory pathology, and mortality have been consistent. Breastfeeding is associated with metabolic and cardiovascular diseases and functionality. Adiposity, bone pathophysiology, functionality in old age, and high blood pressure are associated with socioeconomic status at birth. Several exposures from intrauterine life to adolescence that exert discrete but significant effects on adult health have been consistently described. It is necessary to carry out these studies in developing countries.

Abstract A48: Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis

Abstract The contribution of exposure to the persistent, lipophilic pesticide dichlorodiphenyltrichloroethane (DDT) to breast cancer risk is controversial. A recent report by the International Agency for Research on Cancer (IARC) concluded that no consistent association exists between DDT exposure and breast cancer, yet stressed that there was a lack of existing evidence to allow for the determination of the effects of early-life exposure to DDT. It has been hypothesized that exposure to DDT during critical periods of breast development may increase breast cancer risk. We hypothesized that perinatal DDT exposure would result in shortened latency of spontaneous mammary tumorigenesis and accelerated growth of mammary tumors and increase the incidence of lung metastasis. To test the effect on mammary tumor early progression and growth as well as lung metastasis, C57BL/6J female mice, pregnant as a result of mating with B6.FVB-Tg(MMTV-PyVT)634Mul/LellJ male mice, were administered DDT from gestational day 11.5 to postnatal day 5 to produce circulating levels of DDT in dams within the prenatal range associated with breast cancer in adult daughters. This perinatal DDT exposure significantly accelerated the development of palpable mammary tumors (hazard ratio = 3.7 (95% confidence interval 2.0-6.8; p&amp;lt;0.0001). We also aimed to study possible mechanisms for DDT increasing mammary cancer risk, including alterations in puberty tempo and the presence of breast cancer risk factors associated with impaired metabolism. We found that mice exposed to DDT perinatally had increased terminal end buds in their mammary glands late in puberty (postnatal day 63, p&amp;lt;0.05). Tumor-free mice exposed to DDT perinatally also had significantly elevated circulating glucose levels (p&amp;lt;0.05). The risk of mammary cancer associated with perinatal DDT exposure observed in mice closely mirrors that observed in women previously. Our findings raise the possibility that perinatal DDT exposure may increase risk of breast cancer through its effects on pubertal mammary gland development and/or on glucose homeostasis. Future research to further evaluate whether these effects are mechanisms by which perinatal DDT exposure accelerates breast tumorigenesis is highly warranted. Citation Format: Tomoko Ishikawa, Jason Tong, Alexander Borowsky, Robert Cardiff, Michele La Merrill. Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A48.

The effects of 28-day early-life exposure to triphenyl phosphate (TPhP) on odor preference and sexual behavior in female rats.

Many chemical substances are detectable in house dust, and they are consequently taken into our bodies via the mouth and nose. Triphenyl phosphate (TPhP), a flame retardant that has an estrogen‐like effect in vitro, is present in house dust at high concentrations. Estrogen exposure during development has significant influences on reproductive behavior in rodents, and its effects persist until maturity. In the present study, we investigated the effect of early life exposure to TPhP on the reproductive behavior of female rats. Oral treatment with TPhP (25 or 250 mg/kg), ethinyl estradiol (EE; 15 μg/kg) as a positive control, or sesame oil as a negative control, were given to female rats (from birth to 28 days of age). The 8‐week‐old rats were bilaterally ovariectomized. At 12–15 weeks of age, the rats were subjected to odor preference and sexual behavior tests. In the odor preference test, the oil group showed significantly higher preference for male odor than female odor, but the low‐dose TPhP treatment group lost the preference for male odor, indicating a possible outcome of early life TPhP exposure on sexual recognition. In the sexual behavior test, both the EE and TPhP treatment groups displayed significantly less proceptive behavior. These results suggest that early life exposure to TPhP disturbs the normal sexual behavior of female rats.

Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats

Epidemiological studies link traffic-related air pollution (TRAP) to increased risk for various neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship between TRAP and adverse neurodevelopmental outcomes. Moreover, much of the preclinical literature reports effects of concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of real-world TRAP exposures. To assess the developmental neurotoxicity of more realistic TRAP exposures, we exposed male and female rats during gestation and early postnatal development to TRAP drawn directly from a traffic tunnel in Northern California and delivered to animals in real-time. We compared NDD-relevant neuropathological outcomes at postnatal days 51–55 in TRAP-exposed animals versus control subjects exposed to filtered air. As indicated by immunohistochemical analyses, TRAP significantly increased microglial infiltration in the CA1 hippocampus, but decreased astrogliosis in the dentate gyrus. TRAP exposure had no persistent effect on pro-inflammatory cytokine levels in the male or female brain, but did significantly elevate the anti-inflammatory cytokine IL-10 in females. In male rats, TRAP significantly increased hippocampal neurogenesis, while in females, TRAP increased granule cell layer width. TRAP had no effect on apoptosis in either sex. Magnetic resonance imaging revealed that TRAP-exposed females, but not males, also exhibited decreased lateral ventricular volume, which was correlated with increased granule cell layer width in the hippocampus in females. Collectively, these data indicate that exposure to real-world levels of TRAP during gestation and early postnatal development modulate neurodevelopment, corroborating epidemiological evidence of an association between TRAP exposure and increased risk of NDDs.

Calretinin is a novel candidate marker for adverse ovarian effects of early life exposure to mixtures of endocrine disruptors in the rat

Disruption of sensitive stages of ovary development during fetal and perinatal life can have severe and life-long consequences for a woman’s reproductive life. Exposure to endocrine disrupting chemicals may affect ovarian development, leading to subsequent reproductive disorders. Here, we investigated the effect of early life exposure to defined mixtures of human-relevant endocrine disrupting chemicals on the rat ovary. We aimed to identify molecular events involved in pathogenesis of ovarian dysgenesis syndrome that have potential for future adverse outcome pathway development. We therefore focused on the ovarian proteome. Rats were exposed to a mixture of phthalates, pesticides, UV-filters, bisphenol A, butyl-paraben, and paracetamol during gestation and lactation. The chemicals were tested together or in subgroups of chemicals with anti-androgenic or estrogenic potentials at doses 450-times human exposure. Paracetamol was tested separately, at a dose of 360 mg/kg. Using shotgun proteomics on ovaries from pup day 17 offspring, we observed exposure effects on the proteomes. Nine proteins were affected in more than one exposure group and of these, we conclude that calretinin is a potential key event biomarker of early endocrine disruption in the ovary.

Postnatal zinc or paraquat administration increases paraquat or zinc-induced loss of dopaminergic neurons: insight into augmented neurodegeneration.

Epidemiological evidences have shown an association of exposure to pesticides or heavy metals with increased incidences of Parkinson's disease (PD) in humans. Exposure to pesticides or metals during the decisive period of the brain development increases the susceptibility of dopaminergic neurons upon re-exposure in adult rodents. However, the effect of early life exposure to pesticide on the heavy metal-induced neurodegeneration or heavy metal on pesticide-induced neurodegeneration is not yet explored. The current study explored the effect of developmental exposure to zinc (Zn), a metal or paraquat (PQ), a pesticide on the nigrostriatal dopaminergic neurons of rats challenged to Zn or PQ during adulthood. Exposure of Zn or PQ during adulthood alone exhibited marked reduction in motor activities, striatal dopamine and metabolites, glutathione content and number of dopaminergic neurons. However, the levels of lipid peroxidation, protein carbonyls, superoxide dismutase activity, pro-inflammatory cytokines and 4-hydroxynonenal-protein adducts were increased. While the expression of vesicular monoamine transporter-2 and tyrosine hydroxylase were attenuated, dopamine transporter and microglial marker Iba-1 expression, activated microglia, nuclear factor-kappa B activation, mitochondrial cytochrome c release and caspase-3/9 activation were augmented following Zn or PQ exposure. Albeit postnatal alone exposure did not alter any of the studied parameters, the developmental administration of Zn/PQ in re-challenged adult rats produced more pronounced changes in the aforementioned variables as compared with adulthood Zn or PQ alone intoxicated animals. The results demonstrate that postnatal Zn/PQ intoxication dents the oxidative stress, inflammation, cell death and dopamine metabolism and storage regulating machineries, which speed up the toxicant-induced degeneration during adulthood.