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

ABSTRACT: Developmental exposure to endocrine disrupting chemicals (EDCs), e.g., bisphenol A (BPA) or genistein (GEN), causes longstanding epigenome effects. MicroRNAs (miRs) regulate which mRNAs will be translated to proteins and thereby serve as the final checkpoint in epigenetic control. Scant amount is known, however, whether EDCs affect neural miRNA (miR) patterns. We aimed to test the hypothesis that developmental exposure of California mice (Peromyscus californicus) to GEN, BPA, or both chemicals influences hypothalamic miR/small RNA profiles and ascertain the extent such biomolecular alterations correlate with behavioral and metabolic changes. California mice were developmentally exposed to GEN (250 mg/kg feed weight, FW), GEN (250 mg/kg FW)+BPA (5 mg/kg FW), low dose (LD) BPA (5 mg/kg FW), or upper dose (UD) BPA (50 mg/kg FW). Adult offspring were tested in a battery of behavioral and metabolic tests; whereupon, mice were euthanized, brains were collected and frozen, small RNAs were isolated from hypothalamic punches, and subsequently sequenced. California mice exposed to one or both EDCs engaged in one or more repetitive behaviors. GEN, LD BPA, and UD BPA altered aspects of ultrasonic and audible vocalizations. Each EDC exposure led to sex-dependent differences in differentially expressed miR/small RNAs with miR7-2, miR146, and miR148a being increased in all female and male EDC exposed groups. Current findings reveal that developmental exposure to GEN and/or BPA affects hypothalamic miR/small RNA expression patterns, and such changes correlate with EDC-induced behavioral and metabolic alterations. miR146 is likely an important mediator and biomarker of EDC exposure in mammals, including humans.

SUBMITTER: Kaur S

PROVIDER: S-EPMC7897400 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (∼18-20months) and young (∼4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and reproductive outcomes in young and old breeding adults would be illuminating.

Project description:Sex differences in behavior and morphology are usually assumed to be stronger in polygynous species compared to monogamous species. A few brain structures have been identified as sexually dimorphic in polygynous rodent species, but it is less clear whether these differences persist in monogamous species. California mice are among the 5% or less of mammals that are considered to be monogamous and as such provide an ideal model to examine sexual dimorphism in neuroanatomy. In the present study we compared the volume of hypothalamic- and limbic-associated regions in female and male California mice for sexual dimorphism. We also used tyrosine hydroxylase (TH) immunohistochemistry to compare the number of dopamine neurons in the ventral tegmental area (VTA) in female and male California mice. Additionally, tract tracing was used to accurately delineate the boundaries of the VTA. The total volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA), the principal nucleus of the bed nucleus of the stria terminalis (BNST), and the posterodorsal medial amygdala (MEA) was larger in males compared to females. In the SDN-POA we found that the magnitude of sex differences in the California mouse were intermediate between the large differences observed in promiscuous meadow voles and rats and the absence of significant differences in monogamous prairie voles. However, the magnitude of sex differences in MEA and the BNST were comparable to polygynous species. No sex differences were observed in the volume of the whole brain, the VTA, the nucleus accumbens or the number of TH-ir neurons in the VTA. These data show that despite a monogamous social organization, sexual dimorphisms that have been reported in polygynous rodents extend to California mice. Our data suggest that sex differences in brain structures such as the SDN-POA persist across species with different social organizations and may be an evolutionarily conserved characteristic of mammalian brains.

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

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