Biology subjects

Denys, M. E.

Publications and source records attributed to Denys, M. E..

5 recordsLinked to original sources

bioRxiv2025

Enduring Autism-like Phenotypes and Deregulated Hypothalamic Prosocial Peptides After Early-Life Exposure to Indoor Flame Retardants in Male C57BL/6 Mice

BackgroundPolybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals that produce adverse neurodevelopmental effects. PBDEs have been implicated as risk factors for autism spectrum disorder (ASD), which is characterized by abnormal psychosocial functioning and is commonly accompanied by co-morbidities such as cognitive and attentional deficits. Here, we used a mouse model with translationally relevant exposure to establish direct causal evidence that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in male offspring. MethodsC57Bl6/N mouse dams were exposed to a commercial PBDE mixture, DE-71, via oral administration of 0 (vehicle control, VEH/CON), 0.1 (L-DE-71), or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. ResultsMass spectrometric analysis indicated dose-dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. Adult F1 male offspring displayed ASD-relevant neurobehavioral phenotypes, including impaired short- and long-term social recognition memory (SRM), despite intact general sociability, and exaggerated repetitive behavior. Exposed mice also displayed altered olfactory discrimination of social odors, impaired novel object recognition memory, and reduced open field habituation. However, no changes were observed in anxiety-like, sensorimotor, or depressive-like behaviors relative to VEH/CON. At the molecular level, DE-71 exposed males displayed deregulated gene markers of prosocial neuropeptides. Oxt was upregulated in the paraventricular nucleus (PVN); Avp was upregulated in the PVN and bed nucleus of the stria terminalis (BNST) but downregulated in the lateral septum (LS); Avp1ar and Adcyap1 were upregulated in the BNST; and Adcyap1r1 was upregulated in the PVN, supraoptic nucleus (SON), and BNST. ConclusionsThese findings demonstrate that developmental PBDE exposure produces enduring behavioral and neurochemical phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗

bioRxiv2025

Maternal Thyroid Supplementation Prevents Autistic-relevant Social Behavior and Hypothalamic Oxytocin Depletion Produced by Developmental Exposure to Environmental Toxicants

Environmental toxicants that target the developing brain are suspected of contributing to autism spectrum disorder risk but causative evidence is lacking. We and others have shown that the indoor flame retardants, polybrominated diphenyl ethers (PBDEs), reduce prosocial behavior, however, few studies have assessed the central targets and underlying mechanisms. PBDEs are well established endocrine disruptors of the expanded thyroid system, which also regulates the prosocial neuropeptides oxytocin (OXT) and vasopressin (AVP) and their hypothalamic signaling. The potential role of PBDE-induced thyroid hormone (TH) deregulation in mediating disruption of central OXT and ASD-like social behavior deficits remains unmapped. To address this gap, we conducted a study in C57BL6/N mice that examined behavioral and neuromolecular reprogramming after developmental exposure to the commercial PBDE mixture, DE-71, and evaluated the therapeutic potential of TH supplementation. Dams were exposed daily during gestation and lactation to corn oil vehicle, low dose (0.1 mg/kg) and high dose (0.4 mg/kg) of DE-71 with or without concurrent L-thyroxine (+mT4). In offspring, dose-dependent ASD-relevant behavioral responses and central neuroendocrine OXT neuron depletion after developmental PBDE exposure was prevented with mT4. mRNA transcripts for the TH transporter Mct8, deiodinase (Dio3) and estrogen receptor beta (Esr2) expressed on OXT neurons in PVH were upregulated in low dose females. In contrast, Mct8 and Dio3 were downregulated in low dose males. These findings uncover sex-specific mechanisms of PBDE-induced reprogramming of TH-regulated pathways in hypothalamic neuroendocrine cells leading to depleted central OXT signaling and ultimately ASD-relevant phenotypes. Importantly, we provide novel evidence of the therapeutic potential of maternal thyroid supplementation against toxicant-induced neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Gene Deletion of the PACAP/VIP Receptor, VPAC2R, Alters Glycemic Responses During Metabolic and Psychogenic Stress in Adult Female Mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. These opposing actions need further characterization, as does the role of VIP receptor 2 (VPAC2R) in the regulation of glucose metabolism. In this study, we examined the participation of VPAC2R on basal glycemia, fasted glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/-) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8h overnight fast as compared to wildtype (WT) mice. Insulin tolerance testing following a 5h fast (morning fast, 0.38 U/kg) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/-, but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate the action of upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/-: upregulated medullary tyrosine hydroxylase (Th) and downregulated hypothalamic Vip. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.

physiology↗

bioRxiv2022

Glucoregulatory Reprogramming in Male Mice Offspring Induced by Maternal Transfer of Indoor Flame Retardant Endocrine Disruptors

Polybrominated diphenyl ethers (PBDEs) are commercially used as indoor flame retardants that penetrate biota and bioaccumulate in human tissues, including breast milk. PBDEs have been associated with endocrine disruption, diabetes and metabolic syndrome (MetS) in humans and animals. However, their sex-specific diabetogenic effects are not completely understood. Our past works show diabetogenic effects of the commercial penta-mixture of PBDEs, DE-71, in perinatally exposed C57Bl/6 female mice. As a comparison, in the current study, the effects of DE-71 on glucose homeostasis in male offspring were examined. C57BL/6 dams were exposed to DE-71 at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or received corn oil vehicle (VEH/CON) for a total of 10 wks, including gestation and lactation. Male offspring were examined in adulthood and DE-71 exposure produced hypoglycemia upon extended fasting. In vivo glucose challenge testing showed marked intolerance (H-DE-71) and incomplete clearance (L- and H-DE-71). Moreover, L-DE-71-exposed mice showed altered glucose responses to insulin, especially incomplete glucose clearance and/or utilization. In addition, L-DE-71 produced elevated levels of plasma glucagon and the incretin GLP-1 but no changes were detected on insulin. These alterations, which represent relevant criteria used clinically to diagnose diabetes, were accompanied with reduced hepatic glutamate dehydrogenase enzymatic activity, elevated adrenal epinephrine and decreased thermogenic brown adipose tissue mass, which may indicate several organ system targets of PBDEs. Liver levels of several endocannabinoid species were not altered by perinatal exposure to DE-71 in males. Our findings demonstrate that chronic low exposure to PBDEs in mothers can reprogram glucose homeostasis and glucoregulatory hormones in male offspring. Previous findings using female offspring showed altered glucose homeostasis that aligned with a contrasting diabetogenic phenotype. We summarize the results of the current work generated in males in light of previous findings on females. Taken together, these findings, combined with our prior results, offer a comprehensive account of sex-dependent effects of maternally transferred environmentally relevant PBDEs on glucose homeostasis and glucoregulatory endocrine dysregulation.

pharmacology and toxicology↗

bioRxiv2021

Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display altered short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗