Early Developmental Exposure Research Articles

Exposure to lower temperature during early development decreases hypoxia tolerance in juvenile Fundulus heteroclitus.

Cross-protection occurs when exposure to one stressor confers heightened tolerance against a different stressor. Alternatively, exposure to one stressor could result in reduced tolerance against other stressors. Although cross-protection has been documented in a wide range of taxa at juvenile and adult life stages, whether early developmental exposure to a stressor confers cross-protection or reduced tolerance to other stressors later in life through developmental plasticity remains largely unexplored. In this study, we examined whether altered temperature during embryonic development results in developmental plasticity in upper thermal tolerance or hypoxia tolerance using a small topminnow, Fundulus heteroclitus, and examined potential underlying molecular mechanisms. We incubated embryos at one of two ecologically relevant temperatures (20 °C or 26 °C) until hatch. Once hatched, fish were raised at a common temperature of 20 °C for one year, and tolerance was assessed in both juveniles (6 months) and early adults (1 year). Developmental temperature had no significant effect on thermal tolerance (CTmax) in juvenile fish, or on the transcript abundance of thermal-tolerance related genes (constitutive heat shock proteins, hsc70, hsp90b). In contrast, reduced developmental temperature decreased hypoxia tolerance but increased transcript levels of the hypoxia inducible factor hif1α in juvenile fish but the effects were less evident in older fish. Overall, we found no indication of developmental plasticity for thermal tolerance, but there was evidence of negative impacts of lower developmental temperature on hypoxia tolerance in juveniles associated with changes in gene expression, providing evidence of developmental plasticity across stressors and levels of organization.

Early developmental exposure to heat shock altered the response to handling stress but had limited impacts on the susceptibility to the bacterial pathogen Yersinia ruckeri in juvenile rainbow trout (Oncorhynchus mykiss)

Early developmental exposure to heat shock altered the response to handling stress but had limited impacts on the susceptibility to the bacterial pathogen Yersinia ruckeri in juvenile rainbow trout (Oncorhynchus mykiss)

Integrated Analysis of Neuroendocrine and Neurotransmission Pathways Following Developmental Atrazine Exposure in Zebrafish.

Atrazine is an endocrine-disrupting herbicide, with exposure impacting adverse outcomes along multiple endocrine pathways. This study investigated the neuroendocrine system as the central target of atrazine toxicity, examining effects of early developmental exposures on neurohormones and genes associated with kisspeptin, hypothalamic, pituitary, and dopamine systems. Zebrafish were exposed to 0, 0.3, 3, or 30 ppb (µg/L) atrazine during two developmental time windows. For neurohormone assessments, exposure was ceased at the end of embryogenesis (72 h post-fertilization, hpf) and analyzed immediately or grown to 0.5, 2, or 2.5 years post-fertilization (ypf). Gene expression was measured immediately after 1-72 hpf or 72-120 hpf exposure. Estradiol decreased in the 0.3 and 30 ppb groups in 0.5 ypf female brains, while dopamine decreased in the same treatment groups at 72 hpf. Increases were also observed in 2.5 ypf female brains (3 ppb) for estradiol and in 2 ypf female and male brains (3 and 30 ppb) for dopamine. Gene expression alterations occurred for the follicle-stimulating hormone (fsh) at 72 hpf and the growth hormone (gh1) at 72 and 120 hpf. Overall, results indicated that developmental atrazine exposure has immediate and long-term sex-specific effects on neurohormonal systems.

Developmental exposure of zebrafish to saxitoxin causes altered expression of genes associated with axonal growth

Saxitoxin (STX) is a potent neurotoxin naturally produced by dinoflagellates and cyanobacteria. STX inhibits voltage-gated sodium channels (VGSCs), affecting the propagation of action potentials. Consumption of seafood contaminated with STX is responsible for paralytic shellfish poisoning (PSP). Humans are among the species most sensitive to PSP; neurological symptoms of exposure range from tingling of the extremities to severe paralysis. The objective of this study was to determine the effects of STX exposure on developmental processes during early embryogenesis. This study was designed to test the hypothesis that early developmental exposure to STX would disrupt key processes, particularly those related to neural development. Zebrafish embryos were exposed to STX (24 or 48 pg) or vehicle (0.3 mM HCl) at 6 h post fertilization (hpf) via microinjection. There was no overt toxicity but starting at 36 hpf there was a temporary lack of pigmentation in STX-injected embryos, which resolved by 72 hpf. Using high performance liquid chromatography, we found that STX was retained in embryos up to 72 hpf in a dose-dependent manner. Temporal transcriptional profiling of embryos exposed to 48 pg STX per embryo revealed no differentially expressed genes (DEGs) at 24 hpf, but at 36 and 48 hpf, there were 3547 and 3356 DEGs, respectively. KEGG pathway analysis revealed significant enrichment of genes related to focal adhesion, adherens junction and regulation of actin cytoskeleton, suggesting that cell-cell and cell-extracellular matrix interactions were affected by STX. Genes affected are critical for axonal growth and the development of functional neural networks. We confirmed these findings by visualizing axonal defects in transgenic zebrafish with fluorescently labeled sensory neurons. In addition, our gene expression results suggest that STX exposure affects both canonical and noncanonical functions of VGSCs. Given the fundamental role of VGSCs in both physiology and development, these findings offer valuable insights into effects of exposure to neurotoxins.

Di(2-ethylhexyl) phthalate disrupts circadian rhythm associated with changes in metabolites and cytochrome P450 gene expression in Caenorhabditis elegans

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental pollutant due to its extensive use. While circadian rhythms are inherent in most living organisms, the detrimental effects of DEHP on circadian rhythm and the underlying mechanisms remain largely unknown. This study investigated the influence of early developmental exposure to DEHP on circadian rhythm and explored the possible relationship between circadian disruption and DEHP metabolism in the model organism Caenorhabditis elegans. We observed that DEHP disrupted circadian rhythm in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that DEHP-induced circadian disruption accompanies with altered proportions of DEHP metabolites in C. elegans. RNA sequencing data demonstrated that DEHP-induced circadian rhythm disruption caused differential gene expression. Moreover, DEHP-induced circadian disruption coincided with attenuated inductions of DEHP-induced cytochrome P450 genes, cyp-35A2, cyp-35A3, and cyp-35A4. Notably, cyp-35A2 mRNA exhibited circadian rhythm with entrainment, but DEHP exposure disrupted this rhythm. Our findings suggest that DEHP exposure disrupts circadian rhythm, which is associated with changes in DEHP metabolites and cytochrome P450 gene expression in C. elegans. Given the ubiquitous nature of DEHP pollution and the prevalence of circadian rhythms in living organisms, this study implies a potential negative impact of DEHP on circadian rhythm and DEHP metabolism in organisms.

Diverse PFAS produce unique transcriptomic changes linked to developmental toxicity in zebrafish.

Per- and polyfluoroalkyl substances (PFAS) are a widespread and persistent class of contaminants posing significant environmental and human health concerns. Comprehensive understanding of the modes of action underlying toxicity among structurally diverse PFAS is mostly lacking. To address this need, we recently reported on our application of developing zebrafish to evaluate a large library of PFAS for developmental toxicity. In the present study, we prioritized 15 bioactive PFAS that induced significant morphological effects and performed RNA-sequencing to characterize early transcriptional responses at a single timepoint (48h post fertilization) after early developmental exposures (8h post fertilization). Internal concentrations of 5 of the 15 PFAS were measured from pooled whole fish samples across multiple timepoints between 24-120h post fertilization, and additional temporal transcriptomics at several timepoints (48-96h post fertilization) were conducted for Nafion byproduct 2. A broad range of differentially expressed gene counts were identified across the PFAS exposures. Most PFAS that elicited robust transcriptomic changes affected biological processes of the brain and nervous system development. While PFAS disrupted unique processes, we also found that similarities in some functional head groups of PFAS were associated with the disruption in expression of similar gene sets. Body burdens after early developmental exposures to select sulfonic acid PFAS, including Nafion byproduct 2, increased from the 24-96h post fertilization sampling timepoints and were greater than those of sulfonamide PFAS of similar chain lengths. In parallel, the Nafion byproduct 2-induced transcriptional responses increased between 48 and 96h post fertilization. PFAS characteristics based on toxicity, transcriptomic effects, and modes of action will contribute to further prioritization of PFAS structures for testing and informed hazard assessment.

Effects of developmental exposure to arsenic species on behavioral stress responses in larval zebrafish and implications for stress-related disorders.

Arsenic (As) is globally detected in drinking water and food products at levels repeatedly surpassing regulatory thresholds. Several neurological and mental health risks linked to arsenic exposure are proposed; however, the nature of these effects and their association with the chemical forms of arsenic are not fully understood. Gaining a clear understanding of the etiologies and characteristics of these effects is crucial, particularly in association with developmental exposures where the nervous system is most vulnerable. In this study, we investigated the effects of early developmental exposure (6- to 120-h postfertilization [hpf]) of larval zebrafish to environmentally relevant concentrations of arsenic species-trivalent/pentavalent, inorganic/organic forms-on developmental, behavioral, and molecular endpoints to determine their effect on stress response and their potential association with stress-related disorders. At 120hpf, the developing larvae were assessed for a battery of endpoints including survival, developmental malformities, background activity, and behavioral responses to acute visual and acoustic stimuli. Pooled larval samples were analyzed for alterations in the transcript levels of genes associated with developmental neurotoxicity and stress-related disorders. Developmental exposures at target concentrations did not significantly alter survival, overall development, or background activity, and had minor effects on developmental morphology. Sodium arsenate and monomethylarsonic acid exaggerated the behavioral responses of larval zebrafish, whereas sodium arsenite depressed them. Sodium arsenate induced significant effects on molecular biomarkers. This study highlights the effects of developmental exposure to arsenicals on the behavioral stress response, the role chemical formulation plays in exerting toxicological effects, and the possible association with stress-related disorders.

Effects of developmental exposure to individual and combined PFAS on development and behavioral stress responses in larval zebrafish

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals known for their widespread use and persistence in the environment. Laboratory and epidemiological studies investigating these compounds have signaled their neurotoxic and endocrine-disrupting propensities, prompting further research into their effects on behavioral stress responses and their potential role as risk factors for stress-related disorders such as anxiety and depression. This study elucidates the ramifications of early developmental exposures to individual and combined PFAS on the development and behavioral stress responses of larval zebrafish (Danio rerio), an established model in toxicological research. Wild-type zebrafish embryos were enzymatically dechorionated and exposed to PFOS, PFOA, PFHxS, and PFHxA between 6 and 120 h post-fertilization (hpf). We targeted environmentally relevant concentrations stemming from the USEPA 2016 Hazard Advisory Limit (HAL, 0.07 μg/L) and folds higher (0.35, 0.7, 1.75, and 3.5 μg/L). Evaluations at 120 hpf encompassed mortality, overall development, developmental defects, and larval activity both at baseline stress levels and following exposure to acute stressors (acoustic and visual). Larval exposure to PFOA, PFOS, or PFHxS (0.07 μg/L or higher) elicited significant increases in mortality rates, which capped at 23.1%. Exposure to individual chemicals resulted in limited effects on overall development but increased the prevalence of developmental defects in the body axis, swim bladder, pigmentation, and eyes, as well as the prevalence of yolk sac and pericardial edemas. Larval activity at baseline stress levels and following exposure to acute stimuli was significantly altered. Combined exposure to all four chemicals intensified the breadth of developmental and behavioral alterations, suggesting possible additive or synergistic effects. Our findings shed light on the developmental and neurobehavioral disturbances associated with developmental exposure to PFAS at environmentally relevant concentrations, the added risks of combined exposures to these chemicals, and their possible role as environmental risk factors for stress-related disorders.

Early Developmental Exposure to Triclosan Impacts Fecal Microbial Populations, IgA and Functional Activities of the Rat Microbiome.

Triclosan (TCS), a broad-spectrum antibacterial chemical, is detected in human urine, breast milk, amniotic fluid, and feces; however, little is known about its impact on the intestinal microbiome and host mucosal immunity during pregnancy and early development. Pregnant female rats were orally gavaged with TCS from gestation day (GD) 6 to postpartum (PP) day 28. Offspring were administered TCS from postnatal day (PND) 12 to 28. Studies were conducted to assess changes in the intestinal microbial population (16S-rRNA sequencing) and functional analysis of microbial genes in animals exposed to TCS during pregnancy (GD18), and at PP7, PP28 and PND28. Microbial abundance was compared with the amounts of TCS excreted in feces and IgA levels in feces. The results reveal that TCS decreases the abundance of Bacteroidetes and Firmicutes with a significant increase in Proteobacteria. At PND28, total Operational Taxonomic Units (OTUs) were higher in females and showed correlation with the levels of TCS and unbound IgA in feces. The significant increase in Proteobacteria in all TCS-treated rats along with the increased abundance in OTUs that belong to pathogenic bacterial communities could serve as a signature of TCS-induced dysbiosis. In conclusion, TCS can perturb the microbiome, the functional activities of the microbiome, and activate mucosal immunity during pregnancy and early development.

Replenishment of Drosophila Male Pheromone After Mating.

Insect exocrine gland products can be involved in sexual communication, defense, territory labelling, aggregation and alarm. In the vinegar fly Drosophila melanogaster the ejaculatory bulb synthesizes and releases 11-cis-Vaccenyl acetate (cVa). This pheromone, transferred to the female during copulation, affects aggregation, courtship and male-male aggressive behaviors. To determine the ability of male flies to replenish their cVa levels, males of a control laboratory strain and from the desat1 pheromone-defective mutant strain were allowed to mate successively with several females. We measured mating frequency, duration and latency, the amount of cVa transferred to mated females and the residual cVa in tested males. Mating duration remained constant with multiple matings, but we found that the amount of cVa transferred to females declined with multiple matings, indicating that, over short, biologically-relevant periods, replenishment of the pheromone does not keep up with mating frequency, resulting in the transfer of varying quantities of cVa. Adult responses to cVa are affected by early developmental exposure to this pheromone; our revelation of quantitative variation in the amount of cVa transferred to females in the event of multiple matings by a male suggests variable responses to cVa shown by adults produced by such matings. This implies that the natural role of this compound may be richer than suggested by laboratory experiments that study only one mating event and its immediate behavioral or neurobiological consequences.

Developmental exposure to pesticides that disrupt retinoic acid signaling causes persistent retinoid and behavioral dysfunction in zebrafish.

Early developmental exposure to environmental toxicants may play a role in the risk for developing autism. A variety of pesticides have direct effects on retinoic acid (RA) signaling and as RA signaling has important roles in neurodevelopment, such compounds may cause developmental neurotoxicity through an overlapping adverse outcome pathway. It is hypothesized that a pesticide's embryonic effects on retinoid function may correspond with neurobehavioral disruption later in development. In the current studies, we determined the effects of RA-acting pesticides on neurobehavioral development in zebrafish. Buprofezin and imazalil caused generalized hypoactivity in the larval motility test, whereas chlorothalonil and endosulfan I led to selective hypoactivity and hyperactivity, respectively. With buprofezin, chlorothalonil, and imazalil, hypoactivity and/or novel anxiety-like behaviors persisted in adulthood and buprofezin additionally decreased social attraction responses in adulthood. Endosulfan I did not produce significant adult behavioral effects. Using qPCR analyses of adult brain tissue, we observed treatment-induced alterations in RA synthesis or catabolic genes, indicating persistent changes in RA homeostasis. These changes were compound-specific, with respect to expression directionality, and potential patterns of homeostatic disruption. Results suggest the likely persistence of disruptions in RA signaling well into adulthood and may represent compensatory mechanisms following early life stage exposures. This study demonstrates that early developmental exposure to environmental toxicants that interfere with RA signaling causes short as well as long-term behavioral disruption in a well-established zebrafish behavioral model and expand upon the meaning of the RA adverse outcome pathway, indicating that observed effects likely correspond with the nature of underlying homeostatic effects.

Whole transcriptome analysis in offspring whose fathers were exposed to a developmental insult: a novel avian model

Although the effects of paternal exposure to insults on the offspring received limited attention in the past, it is currently gaining interest especially after understanding the mechanisms which may mediate such exposure effects. In the current study, the well-controlled avian model (Fayoumi) was utilized to investigate the effects of paternal exposure to the developmental insult, chlorpyrifos on the offspring’s gene expression via mRNA and small RNA sequencing. Numerous mRNA gene expression changes were detected in the offspring after paternal exposure to the developmental insult, especially in genes related to neurogenesis, learning and memory. qPCR analysis of several genes, that were significantly changed in mRNA sequencing, confirmed the results obtained in mRNA sequencing. On the other hand, small RNA sequencing did not identify significant microRNA genes expression changes in the offspring after paternal exposure to the developmental insult. The effects of the paternal exposure were more pronounced in the female offspring compared to the male offspring. The results identified expression alterations in major genes (some of which were pertinent to the functional changes observed in other forms of early developmental exposure) after paternal insult exposure and provided a direction for future studies involving the most affected genes.

Developmental exposure of zebrafish to neonicotinoid pesticides: Long-term effects on neurobehavioral function

Neonicotinoid compounds are commonly used insecticides which have become increasingly used as replacements of older generations of insecticides, such as organophosphates. Given the established neurotoxicity of cholinergic toxicants, developmental neurotoxicity studies are needed to identify in vertebrate species the potential toxicity of these insecticides which act on nicotinic cholinergic receptors. Previously, developmental exposure to a neonicotinoid insecticide imidacloprid was shown to cause persisting neurobehavioral toxicity in zebrafish. The current study evaluated neurobehavioral effects of embryonic exposure to two other neonicotinoid insecticides, clothianidin (1–100 µM) and dinotefuran (1–100 µM) in zebrafish (5–120 h post-fertilization), concentrations below the threshold for increased lethality and overt dysmorphogenesis. Neurobehavioral tests were conducted at larval (6 days), adolescent (10 weeks) and adult (8 months) ages. Both compounds caused short-term behavioral effects on larval motility, although these effects were distinct from one another. At a lower concentration (1 µM) clothianidin increased dark-induced locomotor stimulation the second time the lights turned off, while a higher concentration (100 µM) reduced activity in the dark at its second presentation. By contrast, dinotefuran (10–100 µM) caused a general decrease in locomotion. Specific longer-term neurobehavioral toxicity after early developmental exposure was also seen. clothianidin (100 µM) reduced locomotor activity in the novel tank in adolescence and adulthood, as well as reduced baseline activity in the tap startle test (1–100 µM) and reduced activity early (1–10 µM) or throughout the predator avoidance test session (100 µM). In addition to locomotor effects, clothianidin altered the diving response in a dose-, age- and time-block-dependent manner (1 µM, 100 µM), causing fish to remain further away from a fast predator cue (100 µM) relative to controls. Dinotefuran produced comparatively fewer effects, increasing the diving response in adulthood (10 µM), but not adolescence, and suppressing initial locomotor activity in the predator avoidance test (1–10 µM). These data indicate that neonicotinoid insecticides may carry some of the same risks for vertebrates posed by other classes of insecticides, and that these adverse behavioral consequences of early developmental exposure are evident well into adulthood.

Abstract 6458: Maternal and paternal alcohol exposures program higher incidence of hepatocellular carcinoma in offspring

Abstract Environmental exposures during development are known to influence adult health and disease. Specifically, early developmental exposures have been shown to increase susceptibility to cancer in adults through epigenetic mechanisms. Alcohol is a potent environmental carcinogen and teratogen, causing a wide range of health problems across the life course of an individual. Current literature examining early life exposures solely focuses on maternal exposures despite recent efforts to recognize paternal epigenetic contributions. Thus, we investigated the influence of preconception paternal, maternal, and dual parental alcohol exposures on offspring’s predisposition to develop liver disease and hepatocellular carcinoma (HCC). We hypothesized that dual-parental alcohol exposure would exacerbate the incidence of liver cancer in adult offspring. Using an established mouse model, we exposed male and female adult C57BL/6J mice to control (0% EtOH) or alcohol (10% EtOH) preconception treatments. Next, we randomly assigned pups from each treatment to either a single injection of Diethylnitrosamine (DEN; 25mg/kg) to promote liver tumors, or saline control. Finally, we sacrificed offspring on postnatal day 182 and collected organs and blood for enzyme analysis. DEN-treated males display an increased liver-to-body weight ratio compared to saline males while also exhibiting lower body weight. The male progeny from the dual-parental treatment group exhibited a significant increase in tumor incidence and burden in DEN-treated males, exceeding those measured for the maternal and paternal treatments. Further, offspring from the dual-parental group had high levels of alanine transaminase (ALT) and aspartate transaminase (AST) compared to the other treatment groups. Oil Red-O and Sirius Red staining of liver sections revealed increased hepatic steatosis and fibrosis in DEN males compared to saline males. Again, the dual-parental exposed offspring exhibited the most aberrant phenotype. Blind scoring of H&E-stained liver sections identified increases in steatosis, fibrosis, and HCC lesions, with the highest scores emerging in DEN-treated dual-parental offspring. These findings demonstrate that preconception paternal and gestational maternal alcohol exposures program a predisposition to adult-onset chronic diseases including alcoholic fatty liver disease, hepatic fibrosis, and HCC. These experiments not only confirm our hypothesis that dual-parental exposed offspring exhibit an exacerbated hepatic abnormality phenotype, but also highlight the importance of both maternal and paternal environmental exposures on disease risk in offspring. While the negative effects of maternal alcohol consumption have been well established, our novel finding that paternal alcohol exposure also promotes hepatocellular carcinoma in offspring has potentially profound clinical implications. Citation Format: Alison Basel, Sanat S. Bhadsavle, Kara N. Thomas, Katherine N. Zimmel, Alexis N. Roach, Matthew Gaytan, Grace Parkey, Michael C. Golding. Maternal and paternal alcohol exposures program higher incidence of hepatocellular carcinoma in offspring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6458.

Frog hatchlings use early environmental cues to produce an anticipatory resource-use phenotype.

Developmental plasticity can occur at any life stage, but plasticity that acts early in development may give individuals a competitive edge later in life. Here, we asked if early (pre-feeding) exposure to a nutrient-rich resource impacts hatchling morphology in Mexican spadefoot toad tadpoles, Spea multiplicata. A distinctive carnivore morph can be induced when tadpoles eat live fairy shrimp. We investigated whether cues from shrimp--detected before individuals are capable of feeding--alter hatchling morphology such that individuals could potentially take advantage of this nutritious resource once they begin feeding. We found that hatchlings with early developmental exposure to shrimp were larger and had larger jaw muscles--traits that, at later stages, increase a tadpole's competitive ability for shrimp. These results suggest that early developmental stages can assess and respond to environmental cues by producing resource-use phenotypes appropriate for future conditions. Such anticipatory plasticity may be an important but understudied form of developmental plasticity.

Early developmental alcohol exposure alters behavioral outcomes following adolescent re-exposure in a rat model.

Prenatal alcohol exposure alters brain development, affecting cognitive, motor, and emotional domains, and potentially leading to greater alcohol intake during adolescence. The present study investigated whether early alcohol exposure modifies vulnerability to behavioral alterations associated with adolescent alcohol exposure in a rodent model. Sprague-Dawley rats received ethanol or sham intubations during two developmental periods: (1) the third trimester equivalent of brain development in humans (postnatal days [PD] 4-9) and (2) adolescence (PD 28-42). Both exposures resulted in blood alcohol concentrations around 200 mg/dl. Subjects were tested in the open field (PD 45-48) and on hippocampal and prefrontal cortical (PFC) dependent tasks: the Morris water maze (PD 52-58) and trace fear conditioning (PD 63-64). Neonatal alcohol exposure reduced forebrain and cerebellar weight, increased open-field activity, and slowed acquisition of trace fear conditioning. Adolescent alcohol exposure did not disrupt learning or significantly induce gross brain pathology, suggesting that 200 mg/dl/day of ethanol disrupts cognitive development during the 3rd trimester equivalent, but not during adolescence. Interestingly, females exposed to alcohol only during adolescence exhibited an increased conditioned fear response and more rapid habituation of locomotor activity in the open field, suggesting alterations in emotional responding. Moreover, subjects exposed to a combination of neonatal and adolescent alcohol exposure spent significantly more time in the center of the open field chamber than other groups. Similarly, males exposed to the combination exhibited less thigmotaxis in the Morris water maze. These results indicate that combined exposure to alcohol during these two critical periods reduces anxiety-related behaviors and/or increases risk taking in a sex-dependent manner, suggesting that prenatal alcohol exposure may affect risk for emotional consequences of adolescent alcohol exposure.

Neuromorphological and behavioural effects of early developmental exposure to alarm cue on captive-reared Atlantic salmon (Salmo salar)

Behavioural plasticity plays an important role in an organism's ability to adapt to captive settings, but a lack of perceived predation risk during early development in captivity can lead to diminished anti-predator behaviours. Here, we used Atlantic salmon ( Salmo salar) to test whether early developmental exposure to alarm cues (pre-exposure) led to (1) a developmentally plastic response to alarm cue in yearling and (2) an observable change in neural investment. We exposed fry to either a conspecific alarm cue (pre-exposed fish) or control water (non-exposed fish) and measured activity related to anti-predator behaviour such as time spent motionless, number of aggressive acts, and time spent associated with shelter. We found no indication of a developmentally plastic response to early alarm cue exposure, but we found that pre-exposed fish developed relatively smaller olfactory bulbs compared to non-exposed fish. Our results demonstrate the importance of and ability to exploit plastic responses in captive-reared Atlantic salmon and highlight the need to link behaviour with neuromorphological changes.

Factors affecting the biosynthesis and emission of a Drosophila pheromone.

The most studied pheromone in Drosophila melanogaster, cis-vaccenyl acetate (cVA), is synthesized in the male ejaculatory bulb and transferred to the female during copulation. Combined with other chemicals, cVA can modulate fly aggregation, courtship, mating and fighting. We explored the mechanisms underlying both cVA biosynthesis and emission in males of two wild types and a pheromonal mutant line. The effects of ageing, adult social interaction, and maternally transmitted cVA and microbes - both associated with the egg chorion - on cVA biosynthesis and emission were measured. While ageing and genotype changed both biosynthesis and emission in similar ways, early developmental exposure to maternally transmitted cVA and microbes strongly decreased cVA emission but not the biosynthesis of this molecule. This indicates that the release - but not the biosynthesis - of this sex pheromone strongly depends on early developmental context. The mechanism by which the preimaginal effects occur is unknown, but reinforces the significance of development in determining adult physiology and behaviour.

Prenatal and adolescent alcohol exposure programs immunity across the lifespan: CNS-mediated regulation

For many individuals, first exposure to alcohol occurs either prenatally due to maternal drinking, or during adolescence, when alcohol consumption is most likely to be initiated. Prenatal Alcohol Exposure (PAE) and its associated Fetal Alcohol Spectrum Disorders (FASD) in humans is associated with earlier initiation of alcohol use and increased rates of Alcohol Use Disorders (AUD). Initiation of alcohol use and misuse in early adolescence correlates highly with later AUD diagnosis as well. Thus, PAE and adolescent binge drinking set the stage for long-term health consequences due to adverse effects of alcohol on subsequent immune function, effects that may persist across the lifespan. The overarching goal of this review, therefore, is to determine the extent to which early developmental exposure to alcohol produces long-lasting, and potentially life-long, changes in immunological function. Alcohol affects the whole body, yet most studies are narrowly focused on individual features of immune function, largely ignoring the systems-level interactions required for effective host defense. We therefore emphasize the crucial role of the Central Nervous System (CNS) in orchestrating host defense processes. We argue that alcohol-mediated disruption of host immunity can occur through both (a) direct action of ethanol on neuroimmune processes, that subsequently disrupt peripheral immune function (top down); and (b) indirect action of ethanol on peripheral immune organs/cells, which in turn elicit consequent changes in CNS neuroimmune function (bottom up). Recognizing that alcohol consumption across the entire body, we argue in favor of integrative, whole-organism approaches toward understanding alcohol effects on immune function, and highlight the need for more work specifically examining long-lasting effects of early developmental exposure to alcohol (prenatal and adolescent periods) on host immunity.

Maternal exposure to bis(2-ethylhexyl) phthalate during the thyroid hormone-dependent stage induces persistent emotional and cognitive impairment in middle-aged offspring mice

Prenatal DEHP exposure can cause offspring neurodevelopmental toxicity, but the persistent effects of such exposure window are unclear. This study aimed to investigate the lasting neurobehavioral impact of DEHP on offspring following early exposure from GD9.5 (fetal neural tube closure) to GD16.5 (fetal thyroxin, TH, synthesis). Data showed maternal exposure to DEHP during the thyroid hormone-dependent stage induced a range of neurobehavioral phenotypic changes in adult and middle-aged mice, including anxiety, depression and cognitive impairment. Significant reductions in free TH, TH transporters, and TH metabolic enzyme deiodinase II (D2) were observed in the fetal brain, whereas D3 was elevated, indicating that TH signaling disruption was caused by in utero exposure. Gene expression analyses suggested the expression levels of the TH receptors Trα1, Trβ1 and their downstream target, brain-derived neurotrophic factor, were significantly attenuated, which may partially explain the mechanisms of neurodevelopmental impairment. This study provides new evidence of the persistent effects of sex-specific neurodevelopmental impairment due to in utero DEHP exposure, possibly through damage to the fetal brain TH signaling systems that causes lifelong brain damage. These results further suggest a profound neurobehavioral toxicity of DEHP that may be programmed during early developmental stage exposure and manifested later in life.