Critical Developmental Window Research Articles

Wildfire Seasons, Prenatal PM2.5 Exposure, and Respiratory Infections by Age 1 Year: A Population-Based Case-Control Analysis of Critical Developmental Windows

Wildfire Seasons, Prenatal PM_2.5 Exposure, and Respiratory Infections by Age 1 Year: A Population-Based Case-Control Analysis of Critical Developmental Windows

Effects and phenotypic consequences of transient thyrotoxicosis and hypothyroidism at different stages of zebrafish Danio rerio (Teleostei; Cyprinidae) skeleton development.

The effects and consequences of changes in thyroid hormones (THs) level are among the actively studied topics in teleost developmental and evolutionary biology. In most of the experimental models used, the altered hormonal status (either hypo- or hyperthyroidism) is a stable characteristic of the developing organism, and the observed phenotypic outcomes are the cumulative consequences of multiple TH-induced developmental changes. Meanwhile, the influence of the transient fluctuations of TH content on skeleton development has been much less studied. Here, we present experimental data on the developmental effects and phenotypic consequences of transient, pharmacologically induced thyrotoxicosis and hypothyroidism at different stages of ossified skeleton patterning in zebrafish. According to the results, the skeleton structures differed in TH sensitivity. Some showed a notable shift in the developmental timing and rate, while other demonstrated little or no response to changes in TH content. The developmental stages also differed in TH sensitivity. We identified a relatively short developmental period, during which changes in TH level significantly increased the developmental instability and plasticity, leading to phenotypic consequences comparable to those in fish with a persistent hypo- or hyperthyroidism. These findings allow this period to be considered as a critical developmental window.

Gestational and postnatal exposure to wildfire smoke and prolonged use of respiratory medications in early life

As wildfire frequency and severity increases, smoke exposures will cause increasingly more adverse respiratory effects. While acute respiratory effects of smoke exposure have been documented in children, longer term sequelae are largely unstudied. Our objective here was to examine the association between gestational and postnatal exposure to wildfire smoke and prolonged use of prescription medication for respiratory conditions in early childhood. Using Merative MarketScan claims data, we created cohorts of term children born in western states between 1 January 2010-31 December 2014 followed for at least three years. Using NOAA Hazard Mapping System data, we determined the average number of days a week that >25% of the population in a metropolitan statistical area (MSA) was covered by smoke within each exposure period. The exposure periods were defined by trimester and two 12 week postnatal periods. Medication use was based on respiratory indication (upper respiratory, lower respiratory, or any respiratory condition) and categorized into outcomes of prolonged use (⩾30 d use) (PU) and multiple prolonged uses (at least two prolonged uses) (MPU). We used logistic regression models with random intercepts for MSAs adjusted for child sex, birth season, and birth year. Associations differed by exposure period and respiratory outcome, with elevated risk of MPU of lower respiratory medications following exposure in the third trimester and the first 12 postnatal weeks (RR 1.15, 95% CI 0.98, 1.35; RR 1.21, 95% CI 1.05, 1.40, respectively). Exposure in the third trimester was associated with an increase in MPU of any respiratory among males infants only (male RR 1.22, 95% CI 1.00, 1.50; female RR 0.93, 95% CI 0.66, 1.31). Through novel use of prescription claims data, this work identifies critical developmental windows in the 3rd trimester and first 12 postnatal weeks during which environmental inhalational disaster events may impact longer-term respiratory health.

Developmental exposures to common environmental pollutants result in long-term Reprogramming of hypothalamic-pituitary axis in mice

Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), or 3,3′,5,5′-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level.

A developmental neurotoxicity adverse outcome pathway (DNT-AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE).

The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence-based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified.

Limited Bedding and Nesting as a Model for Early-Life Adversity in Mice.

Early-life adversity (ELA), such as abuse, neglect, lack of resources, and an unpredictable home environment, is a known risk factor for developing neuropsychiatric disorders such as depression. Animal models for ELA have been used to study the impact of chronic stress on brain development, and typically rely on manipulating the quality and/or quantity of maternal care, as this is the major source of early-life experiences in mammals, including humans. Here, a detailed protocol for employing the Limited Bedding and Nesting (LBN) model in mice is provided. This model mimics a low-resource environment, which provokes fragmented and unpredictable patterns of maternal care during a critical developmental window (postnatal days 2-9) by limiting the amount of nesting materials given to the dam to build a nest for her pups and separating the mice from the bedding via a mesh platform in the cage. Representative data are provided to illustrate the changes in maternal behavior, as well as the diminished pup weights and long-term changes in basal corticosterone levels, that result from the LBN model. As adults, offspring rearedin the LBN environment have been shown to exhibit an aberrant stress response, cognitive deficits, and anhedonia-like behavior. Therefore, this model is an important tool to define how the maturation of stress-sensitive brain circuits is altered by ELA and results in long-term behavioral changes that confer vulnerability to mental disorders.

“As Long as There’s a Glimmer of Hope, I’m Willing to Try”: The Moral Experiences of Parental Pursuit for Autism Therapy in Urban China

ABSTRACT In today’s China, countless parents embark on a journey of moral peril in search of treatment for their children with autism, navigating a bustling yet chaotic market of therapies. Based on 13 months of fieldwork in the Pearl River Delta, this study examines how the boom of China’s autism therapy industry has plunged parents, who are relentlessly striving for their children’s futures, into deeper vulnerability. I view the “ethics of trying” as parental enactment of their moral agency in seeking therapy and reveal how it serves as a moral engine for the industry’s growth in the early 21st century, as well as how it leads to moral tragedies for parents as new norms of therapeutic choice emerge with government and professional guidance compelling them to make optimal therapeutic choices within a critical developmental window. Although parental efforts to avoid “agent-regret” can paradoxically lead to significant remorse, the moral tragedy they encounter can also prompt reflection and reevaluation of their approach to their child’s condition.

A Case Study Applying Cognitive Processing Therapy to Childbirth-Related PTSD: Treatment Considerations for the Postpartum Period

In sharp contrast to societal narratives framing the birth of a new baby as a time of unequivocal joy, childbirth-related trauma is relatively common and can result in postpartum PTSD. Research indicates that postpartum PTSD can have serious psychosocial implications during the perinatal period, a known critical developmental window shaping child and maternal heath across the lifespan. However, empirical research on the effectiveness of specific treatment approaches for childbirth-related trauma remains limited. Given the extensive effects and prevalence of postpartum PTSD, determining effective treatment options is a high priority. Cognitive Processing Therapy (CPT) is a gold-standard evidence-based psychotherapy for PTSD that has not been evaluated in the context of postpartum PTSD, and may be particularly well-suited for treating birth trauma. In the current case study, we describe the assessment and treatment of childbirth-related PTSD using CPT. By the end of the 14-session therapy course, the patient experienced a reduction in symptoms (City Birth Trauma Scale score dropped from 38 to 14), associated distress, and functional impairment. This case study suggests that CPT is an effective treatment for postpartum PTSD. We conclude with considerations to guide future research and treatment efforts.

Anthropometric Influence on Preschool Children's Physical Fitness and Motor Skills: A Systematic Review.

Early childhood is a critical period for physical and motor development with implications for long-term health. This systematic review examined the relationship between anthropometric characteristics and measures of physical fitness and motor skills in preschool-aged children (typically 2-6 years). The search strategy was applied in four databases (PubMed, ProQuest Central, Scopus, and Web of Science) to find articles published before 11 April 2024. The results consistently demonstrated significant associations between anthropometric variables (height, weight, body mass index [BMI], body composition) and physical performance measures. Notably, height and mass were often better predictors of fitness status than BMI alone. Indicators of undernutrition (stunting, wasting) were negatively associated with motor development, emphasizing the importance of adequate nutrition. While some studies reported impaired fitness and motor skills among overweight/obese preschoolers compared to normal-weight peers, others found no differences based on weight status. Relationships between physical activity levels, anthropometrics, and motor outcomes were complex and inconsistent across studies. This review highlights key findings regarding the influence of anthropometric factors on physical capabilities in early childhood. Early identification of children with impaired growth or excessive adiposity may inform tailored interventions to promote optimal motor development and prevent issues like obesity. Creating supportive environments for healthy growth and age-appropriate physical activity opportunities is crucial during this critical developmental window.

Obesogens in Adolescence: Challenging Aspects and Prevention Strategies.

Childhood obesity has become a global epidemic, with significant increases in prevalence over recent decades. While excessive calorie consumption and physical inactivity are known factors, emerging research highlights the role of endocrine-disrupting chemicals (EDCs), particularly obesogens, in obesity's pathogenesis. This review explores the historical context of the environmental obesogens hypothesis, their sources, mechanism of action, impact on prenatal and postnatal development, and epigenetics. Additionally, it discusses the long-term consequences of childhood obesity and proposes prevention strategies that will mitigate negative health effects. Obesogens were found to disrupt hormonal balance and metabolic processes through various mechanisms such as altering gene expression, hormonal interference, and inflammation. Especially significant was exposure during critical windows of development, which correlates with an increased risk of obesity in childhood or adolescence. Long-term effects of childhood obesity include chronic health conditions and psychosocial issues. A comprehensive approach is necessary to address childhood obesity encompassing genetic, environmental, and lifestyle factors. Prevention strategies should focus on reducing obesogen exposure, promoting healthy lifestyles, and implementing regulatory policies. Future research should investigate obesogens-diet interactions, microbiome impacts, and combined obesogens effects. Long-term human studies are also crucial for validating findings from animal models and allowing for informed decision-making to combat the obesity pandemic.

Children's food allergy: Effects of environmental influences and antibiotic use across critical developmental windows

BackgroundIncreasing studies linked outdoor air pollution (OAP), indoor environmental factors (IEFs), and antibiotics use (AU) with the first wave of allergies (i.e., asthma, allergic rhinitis, and eczema), yet the role of their exposures on children’s second wave of allergy (i.e., food allergy) are unknown. ObjectivesTo investigate the association between exposure to OAP and IEFs and childhood doctor-diagnosed food allergy (DFA) during the pre-pregnancy, prenatal, early postnatal, and current periods, and to further explore the effect of OAP and IEFs on DFA in children co-exposed to antibiotics. MethodsA retrospective cohort study involving 8689 preschoolers was carried out in Changsha, China. Data on the health outcomes, antibiotic use, and home environment of each child were collected through a questionnaire. Temperature and air pollutants data were obtained from 8 and 10 monitoring stations in Changsha, respectively. Exposure levels to temperature and air pollutants at individual home addresses were calculated by the inverse distance weighted (IDW) method. Multiple logistic regression models were employed to assess the associations of childhood DFA with exposure to OAP, IEF, and AU. ResultsChildhood ever doctor-diagnosed food allergy (DFA) was linked to postnatal PM10 exposure with OR (95% CI) of 1.18 (1.03–1.36), especially for CO and O3 exposure during the first year with ORs (95% CI) = 1.08 (1.00–1.16) and 1.07 (1.00–1.14), as well as SO2 exposure during the previous year with OR (95% CI) of 1.13 (1.02–1.25). The role of postnatal air pollution is more important for the risk of egg, milk and other food allergies. Renovation-related IAP (new furniture) and dampness-related indoor allergens exposures throughout all time windows significantly increased the risk of childhood DFA, with ORs ranging from 1.23 (1.03–1.46) to 1.54 (1.29–1.83). Furthermore, smoke-related IAP (environmental tobacco smoke [ETS], parental and grandparental smoking) exposure during pregnancy, first year, and previous year was related to DFA. Additionally, exposure to pet-related indoor allergens (cats) during first year and total plant-related allergens (particularly nonflowering plants) during previous year were associated with DFA. Moreover, exposure to plant-related allergy during first and previous year was specifically associated with milk allergy, while keeping cats during first year increased the risk of fruits/vegetables allergy. Life-time and early-life AU was associated with the increased risk of childhood DFA with ORs (95% CI) = 1.57 (1.32–1.87) and 1.46 (1.27–1.67), including different types food allergies except fruit/vegetable allergy. ConclusionsPostnatal OAP, life-time and early-life IEFs and AU exposure played a vital role in the development of DFA, supporting the "fetal origin of childhood FA" hypothesis.

The Impacts of Osmotic Stress During the Critical Window of Development on Protein and Histone PTM Alterations in California grunion

The California Grunion, Leuresthes tenuis, can experience a broad range of salinities during their early life stages, with their nursery grounds measuring salinities of 21 to 42ppt under normal conditions. Due to the unique subterrestrial incubation of their eggs within the sand of California beaches, it is not unlikely for this marine fish to hatch in non-seawater conditions, whereafter the larvae may transition to relatively diluted estuaries or concentrated harbors to develop as juveniles for several months. Consequently, they are an ideal system to study the impacts of ecologically relevant salinity stress on the alteration of proteins and histone post-translational modifications (PTMs) during early development. The study of the relationship between the critical window of development (CWD), in which sexual bipotential is lost, and the longevity of protein landscape and histone PTM changes has not been widely explored. The CWD is of interest as this is when the gametes of this species become set. Therefore, we hypothesize that histone PTM changes that occur during this time may thus be a form of heritable epigenetics. Thus, hypo-and-hyperosmotic exposures of L. tenuis hatchlings during this window, and past it, attempt to identify if the CWD is relevant to the presence and persistence of protein and histone PTM changes under salinity stress. We hypothesize that exposure to osmotic stress during the CWD will result in induced compensatory mechanisms in the protein landscape of the California grunion larvae, as well as persistent alterations in the histone PTMs in the larvae. To elucidate the relationship between these factors, California grunion larvae were exposed in replicate to one of three chronic salinity treatments (16ppt, 32ppt, or 40ppt) for the duration of their CWD (68dph), with 16ppt and 40ppt inducing hypoosmotic and hyperosmotic stress respectively. Chronic post-CWD exposures and recovery times until 98dph were used to determine whether the CWD or prolonged salinity exposures were key to alterations in the histone PTM and protein landscape of the larvae. After each timepoint, L. tenuis were culled and processed for histone PTM enrichment and proteomic analysis. At the time of culling, there were no significant differences in survivorship between replicates and experimental groups, with statistically significant different deaths between groups occurring only shortly after hatching. Skyline and MSstats were used in the analysis of the statistical significance of differential regulation of proteins and histone PTMs under stress conditions versus the controls. Of special interest is the osmoregulatory mechanisms involved in the myo-inositol biosynthesis pathway, with analysis focusing on the abundance of histone acetylation, amidation, ubiquitylation, and 4-hydroxynonelation in histone PTMs, as the accumulations of these have been found to be correlated with osmotic stress in some fish tissues. Funding provided by NSF IOS-2209383 and NSF GRFP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Early-life inflammation increases ethanol consumption in adolescent male mice

Recent studies have demonstrated that stress during the critical windows of development can evoke a cascade of neurological changes that can result in neuropsychiatric disorders later in life. In this study, we examined the effect of early-life inflammation on ethanol consumption in adolescent mice. C57BL/6J mice were assigned to either the control or Lipopolysaccharide (LPS) group on postnatal day 14 (P14). In the latter group, LPS at a dose of 50 μg/kg was injected intraperitoneally. The mice were weaned at P21, and behavior tests were performed at P45. Ethanol consumption was assessed using a two-bottle choice drinking paradigm. Anxiety-like behaviors were assessed by marble burying test (MBT), open field (OF), and elevated plus maze (EPM). Ethanol-induced loss of righting reflex (LORR), hypothermia and ethanol metabolism were assessed to evaluate ethanol intoxication. P14 LPS-injected adolescent male mice exhibited significantly increased ethanol preference and consumption, with a similar taste preference for saccharin and avoidance of quinine. The adolescent male mice showed increased anxiety-like behaviors in the OF and EPM tests, and an increased duration of LORR, without affecting the hypothermic effects of ethanol and ethanol metabolism. Interestingly, these behavioral changes were not obvious in female mice. In conclusion, our data indicate that early-life inflammation may be a risk factor for ethanol consumption in adolescents with greater changes observed in male mice. Significance StatementOur study is the first preclinical model to report the enhancement effect of early-life inflammation on ethanol consumption in adolescent male mice and our findings provide a valuable mouse model to examine the neurobiological mechanisms mediating the long-lasting effects of early-life inflammation on alcohol use disorders vulnerability.

The presence of predators constrains larval development process by influencing critical developmental windows in the endangered Chinhai spiny newt.

Predators significantly impact the development process and subsequently influence the metamorphic decisions of amphibian larvae. Larvae often exhibit induced growth and metamorphic plasticity in response to the presence of predators. However, growth and development rates are not always perfectly correlated, growth responses can vary throughout ontogeny. It is crucial to consider the stage-specific growth responses induced by predators. Here, we employ a critical windows experimental design and examine development-related growth and metamorphic responses to predators in the endangered Chinhai spiny newt (Echinotriton chinhaiensis). Our findings reveal that predators constrain the development process of spiny newt larvae and also impact survival to metamorphosis. Inducible plasticity predominantly exhibits in the early and middle stages of larval development. Our results also suggest that diverse developmental plasticity has been adopted by larvae in response to predators. The presence of predators during early stage induces larvae to exhibit a same size at metamorphosis but a prolonged time to metamorphosis, while predators present during middle stage induce larvae to exhibit a large size at metamorphosis but a same time to metamorphosis. The presence of predators at the late developmental stage does not induce any plasticity in larval growth and metamorphosis. Moreover, these results also suggest that several stages of larval development are likely critical developmental windows for spiny newt larvae. This study not only provides basic biological information on predator-induced developmental plasticity of the endangered Chinhai spiny newt but also likely provides biological insights for the implementation of insitu conservation and preservation efforts for endangered species.

Reconstructing axial progenitor field dynamics in mouse stem cell-derived embryoids

Embryogenesis requires substantial coordination to translate genetic programs to the collective behavior of differentiating cells, but understanding how cellular decisions control tissue morphology remains conceptually and technically challenging. Here, we combine continuous Cas9-based molecular recording with a mouse embryonic stem cell-based model of the embryonic trunk to build single-cell phylogenies that describe the behavior of transient, multipotent neuro-mesodermal progenitors (NMPs) as they commit into neural and somitic cell types. We find that NMPs show subtle transcriptional signatures related to their recent differentiation and contribute to downstream lineages through a surprisingly broad distribution of individual fate outcomes. Although decision-making can be heavily influenced by environmental cues to induce morphological phenotypes, axial progenitors intrinsically mature over developmental time to favor the neural lineage. Using these data, we present an experimental and analytical framework for exploring the non-homeostatic dynamics of transient progenitor populations as they shape complex tissues during critical developmental windows.

Early life phenobarbital exposure dysregulates the hippocampal transcriptome.

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte- associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.

Altered Trajectories: Considering the Long-Term Impact of Educational Disruption during the COVID-19 Pandemic on Neurodevelopment and a Call to Action for Neuropsychology.

The COVID-19 pandemic resulted in educational disruption of historic breadth and duration. The impact of school closures and remote learning have been evaluated in recent studies and reflect critical data for neuropsychologists who routinely assess brain development as it relates to diagnosis, recommendations, and informing public policy. Pre-pandemic and contemporaneous literature was summarized, including data on educational disruption and child and adolescent mental health challenges reported during the pandemic, and research on the impact of stress, social isolation, educational achievement, and other factors on brain development during critical developmental windows. Studies indicate that prolonged educational disruption has resulted in attenuated learning gains, most remarkably for those already at risk for educational disparities. Studies have shown increased mental health challenges for youth during the pandemic, with higher rates of mood and eating disorders, and suicidal ideation. Given that some skills develop optimally within specific time periods, pandemic-related disruption has likely contributed to altered developmental trajectories. Trajectory of neuropsychological development of children and adolescents, especially marginalized students, may be affected by effects on learning and mental health due to prolonged educational disruption and psychological stressors. Evaluation and treatment may be delayed due to backlog and increased demand. Clinical neuropsychological practice recommendations are presented with a call to action for the field in moving forward flexibly to increase access to evaluation services.

PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women

BackgroundPyrethroids are widely used pesticides and are suspected to affect children's neurodevelopment. The characterization of pyrethroid exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of pyrethroids potential effects within the concept of Developmental Origins of Health and Disease. ObjectiveThe aim of this study was to estimate maternal exposure of French pregnant women from biomonitoring data and simulate maternal and fetal internal concentrations of 3 pyrethroids (permethrin, cypermethrin and deltamethrin) using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. The estimated maternal exposures were compared to newly proposed toxicological reference values (TRV) children specific also called draft child-specific reference value to assess pyrethroid exposure risk during pregnancy i.e. during the in utero exposure period. MethodsA pregnancy-PBPK model was developed based on an existing adult pyrethroids model. The maternal exposure to each parent compound of pregnant women of the Elfe (French Longitudinal Study since Childhood) cohort was estimated by reverse dosimetry based on urinary biomonitoring data. To identify permethrin and cypermethrin contribution to their common urinary biomarkers of exposure, an exposure ratio based on biomarkers in hair was tested. Finally, exposure estimates were compared to current and draft child-specific reference values derived from rodent prenatal and postnatal exposure studies. ResultsThe main contributor to maternal pyrethroid diet intake is cis-permethrin. In blood, total internal concentrations main contributor is deltamethrin. In brain, the major contributors to internal pyrethroid exposure are deltamethrin for fetuses and cis-permethrin for mothers. Risk is identified only for permethrin when referring to the draft child-specific reference value. 2.5% of the population exceeded permethrin draft child-specific reference value. ConclusionsA new reverse dosimetry approach using PBPK model combined with human biomonitoring data in urine and hair was proposed to estimate Elfe pregnant population exposure to a pyrethroids mixture with common metabolites.

Dopaminergic Remodeling During a Critical Developmental Window: Linking Drug Use to Adult Aggression.

Dopaminergic Remodeling During a Critical Developmental Window: Linking Drug Use to Adult Aggression.

Maternal-driven immune education in offspring.

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal-offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota-derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue-specific immune education to offspring. We propose a "maternal-driven immune education" hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.