Endocrine Disrupting Chemicals, Epigenetic Alterations, and Autism-Like Behaviors in the Highly Social California Mouse Model

高度社会化加州小鼠模型中的内分泌干扰化学物质、表观遗传改变和自闭症样行为

• 批准号: 10016304
• 负责人: R. MICHAEL ROBERTS
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016304
• 关键词: Adult; Affect; Affective; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Brain; Brain region; California; Candidate Disease Gene; Categories; Chemicals; Child; Clinical; Cognitive; Cognitive deficits; DNA Methylation; Data; Deer Mouse; Development; Diagnosis; Disease; Dose; Endocrine Disruptors; Environmental Risk Factor; Epigenetic Process; Equipment; Estrogens; Ethinyl Estradiol; Etiology; Exhibits; Exposure to; Female; Gene Expression; Genes; Genetic; Genistein; Goals; Hand; Hippocampus (Brain); Human; Hypothalamic structure; Impairment; Incidence; Individual; Infant formula; International; Link; Measures; MicroRNAs; Mothers; Mus; Parents; Pathway Analysis; Pathway interactions; Patients; Pattern; Perinatal Exposure; Peromyscus; Phytoestrogens; Plants; Process; Reporting; Research; Risk; Rodent; Same-sex; Sex Behavior; Siblings; Societies; Statistical Data Interpretation; Study models; Testing; Transgenic Mice; Translating; anxiety-like behavior; autism spectrum disorder; autistic children; base; behavioral phenotyping; bisphenol A; candidate marker; disorder risk; environmental chemical; experience; in utero; male; methylation pattern; mother nutrition; mouse model; neurobehavioral; neurobehavioral disorder; novel; offspring; prenatal exposure; relating to nervous system; remediation; repetitive behavior; sex; social; social organization; soy; steroid hormone; trait; transcriptome; transcriptomics; treatment group; way finding

Project Summary Increasing numbers of children are being diagnosed with autism spectrum disorders (ASD and related neurobehavioral disorders. Based on the rising incidence that is not explained by genetics alone, it has been postulated that in utero exposure to environmental chemicals may increase the risk for these disorders. Perinatal exposure of children through the mother to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), has been linked to ASD. To establish potential causation and underlying mechanisms, it is important to test these chemicals in a relevant animal model species, where the clinical core behavioral symptoms exhibited by ASD children can be replicated. Most ASD animal model studies to date have employed transgenic mice. However, these animals often fail to replicate all of the core ASD-like behaviors. The monogamous, biparental, and highly communicative California mouse (Peromyscus californicus) provides a complementary animal model for ASD research. We have previously demonstrated that neurobehavioral programming in California mice is especially vulnerable to BPA. Developmentally exposed males demonstrate compromised socio-sexual behaviors, and their female siblings exhibit heightened anxiety, reminiscent of children with ASD. Both males and females developmentally exposed to BPA go on to become poor parents as adults. We will test the hypothesis that early exposure to BPA and genistein (G), a phytoestrogen present in soy products- including baby formulas, results in ASD-like behavioral disorders in California mice. The first goal will be to ascertain whether early exposure to BPA, G, and the combination of the two EDCs results in behavioral deficits observed in ASD patients. The second goal will be to determine whether males and females exposed to these chemicals show gene expression/DNA methylation/miRNA (miR) changes in the brain sub- regions (amygdala, hypothalamus and hippocampus) governing these traits that may underlie the disrupted behavioral phenotypes. Specific Aims are to: 1) Test whether developmental exposure of male and female F1 California mice to BPA, G, and BPA + G affects behavioral domains disrupted in ASD children, such as social-sexual-communicative, cognitive, anxiety/neuro-affective, and repetitive behaviors. 2) Test whether these individual and combined EDCs affect global transcriptomic profiles in the amygdala, hippocampus and hypothalamus in F1 males and females that may underpin the EDC-induced behavioral disruptions. 3) Determine whether these treatments induce DNA methylation and miR changes in the amygdala, hippocampus and hypothalamus in both F1 sexes and perform a comprehensive correlation analysis to link the various bio-molecular and behavioral disturbances. Data will likely provide novel candidate biomarkers that can be used to diagnose and in potential preventative/remediation strategies in children at-risk for ASD due to early exposure to these EDCs.

项目总结

项目成果

Brain Sexual Differentiation and Requirement of SRY: Why or Why Not?

• DOI: 10.3389/fnins.2017.00632
• 发表时间: 2017
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Rosenfeld CS

Long-Term Effects of Developmental Exposure to Oxycodone on Gut Microbiota and Relationship to Adult Behaviors and Metabolism.

• DOI: 10.1128/msystems.00336-22
• 发表时间: 2022-08-30
• 期刊: mSystems
• 影响因子: 6.4

Placental Changes in the serotonin transporter (Slc6a4) knockout mouse suggest a role for serotonin in controlling nutrient acquisition.

• DOI: 10.1016/j.placenta.2021.09.021
• 发表时间: 2021-11
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Mao J;Kinkade JA;Bivens NJ;Roberts RM;Rosenfeld CS
• 通讯作者: Rosenfeld CS

Disruption of global hypothalamic microRNA (miR) profiles and associated behavioral changes in California mice (Peromyscus californicus) developmentally exposed to endocrine disrupting chemicals.

• DOI: 10.1016/j.yhbeh.2020.104890
• 发表时间: 2021-03
• 期刊: Hormones and behavior
• 影响因子: 3.5
• 作者: Kaur S;Kinkade JA;Green MT;Martin RE;Willemse TE;Bivens NJ;Schenk AK;Helferich WG;Trainor BC;Fass J;Settles M;Mao J;Rosenfeld CS
• 通讯作者: Rosenfeld CS

Sexually Dimorphic Effects of Aromatase on Neurobehavioral Responses.

• DOI: 10.3389/fnmol.2018.00374
• 发表时间: 2018
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Shay DA;Vieira-Potter VJ;Rosenfeld CS
• 通讯作者: Rosenfeld CS