Persistent autism-relevant behavioral phenotype and social neuropeptide alterations in female mice offspring induced by maternal transfer of PBDE congeners in the commercial mixture DE-71

Abstract

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 end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in 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 deficient 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, and 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.

Developmental exposure to indoor flame retardants and hypothalamic molecular signatures: Sex-dependent reprogramming of lipid homeostasis

“…Female dams do not display altered hypercholesterolemia nor diabetogenic phenotype thus, adults are less susceptible to DE-71 exposure relative to offspring. Our previous findings also indicate elevated plasma vasopressin in L-DE-71 female offspring ( 34 ); elevated vasopressin (as measured by its stable surrogate marker copeptin) is positively associated with hepatic steatosis and MetS ( 86 ). The effects produced by developmental exposure to DE-71 have been incorporated into a possible adverse outcome pathway that describes key events leading to physiological and organismal outcomes such as MetS, T2D, fatty liver disease and cardiovascular disease ( Figure 7 ).…”

“…The present study provides the first evidence of an environmentally relevant PBDE mixture on lipid metabolism and potential associated central mechanisms ( 34 ). Specifically, lipid parameters in exposed female offspring were compared to those obtained from their male counterparts and their mothers.…”

“…The DE-71 doses were selected to contain the same molar concentrations of BDE-47 used in other mouse studies ( 24 , 33 ). This exposure regimen involving maternal transfer to offspring yields accumulation of BDE congeners in offspring at ppm concentrations in liver (.2-1.0) and brain (.07-.3) ( 16 , 34 ). In toddlers, ∑PBDE values in plasma have been reported to range from .1-.5 ppm.…”

“… Fwd, forward; Rv, reverse; E, primer efficiency; Tm, melting temperature; bp; base pair. Primer sequences were obtained from: a ( 44 ); b ( 34 ); c ( 45 ). N/A, near upstream in-frame codon.…”

Deeply in Plasticenta: Presence of Microplastics in the Intracellular Compartment of Human Placentas

“…Exposure to Polybrominated diphenyl ethers during intrauterine development produces neurochemical, olfactory, and behavioral processes that are relevant and very similar to those of autism spectrum disorders (ASD) in humans. These effects can reprogram early neurological development within central memory and social networks [ 37 ]. Oral administration of monodispersed polystyrene also causes damage to the visceral organs in mice.…”