Widespread patterns of sexually dimorphic gene expression in an avian hypothalamic–pituitary–gonadal (HPG) axis

MacManes, Matthew D.; Austin, Suzanne H.; Lang, Andrew S.; Booth, April M.; Farrar, Victoria S.; Calisi, Rebecca M.

doi:10.1101/085365

Cited by 12 publications

(23 citation statements)

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“…The decrease in alternative splicing events experienced by stressed males and females as compared to their unstressed controls may suggest that both sexes are converging 660 on an optimal splicing landscape. Previous reports show differential gene expression (DGE) between sexes in both an unstressed control state (Shapiro et al, 2013;Gillespie et al, 2013;MacManes et al, 2017), and in response to a stressor (Shapiro et al, 2013;Gillespie et al, 2013;MacManes et al, 2017;Calisi et al, 2018). Given these previous findings, coupled with ours presented here, we suggest that future study of the 665 HPG stress response should endeavor to further characterize sex-specific and sexconvergent responses at all levels -genomic, proteomic, and methylomic.…”

Section: Convergent Landscape Hypothesissupporting

confidence: 81%

“…Trunk blood was collected for the detection of concentrations of the adrenal hormone, corticosterone; high concentrations confirmed the effectiveness of the stress treatment protocol (Calisi et al, 2018). All tissues (brains, pituitaries, and gonads) were flash frozen on dry ice and transferred to a -80 • C freezer for storage until additional processing, a process described in (Shapiro et al, 2013;Gillespie et al, 2013;MacManes et al, 2017;Calisi et al, 2018). Briefly, a cryostat (Leica CM 1860) was used to section the brains coronally at 100 microns to enable optimal visualization and biopsy of the hypothalamus, which included the adjoined lateral septum.…”

Section: Animal Collectionmentioning

confidence: 99%

“…cDNA Library Preparation and Sequencing Library preparation and sequencing has been previously described in (Shapiro et al, 2013;Gillespie et al, 2013;MacManes et al, 2017;Calisi et al, 2018). In brief, all tissue samples were thawed on ice in an RNAse-free work environment.…”

Section: Animal Collectionmentioning

confidence: 99%

“…In vertebrates, a symphony of physiological events is required to regulate sexual behavior and reproduction, and these mechanisms are driven by an interconnected biological system made up of the hypothalamus in the brain, the pituitary gland, and the gonads (testes/ovaries) (Sower, Freamat & Kavanaugh, 2009;Nozaki, 2013;MacManes et al, 2017;Calisi et al, 2018). This hypothalamic-pituitary-gonadal (HPG) axis can be disrupted in multiple, complex ways (Johnson et al, 1992;Toufexis et al, 2014;Geraghty & Kaufer, 2015;Calisi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Using the classic reproductive model (Darwin, 1860;Lehrman, 1955;Ball & Silver, 1983;Buntin, Ruzycki & Witebsky, 1993) and rising genomics model (Shapiro et al, 2013;Gillespie et al, 2013;Domyan et al, 2016;MacManes et al, 2017;Calisi et 155 al., 2018) of the rock dove, Columba livia, we have identified sexual dimorphism in both basal (MacManes et al, 2017) and restraint stress-responsive (Calisi et al, 2018) HPG gene expression at the level of RNA transcription. In this study, we traverse beyond the level of transcription to test for sex-biased alternative splicing patterns in the HPG axis of the rock dove in response to a restraint stress stimulus.…”

Section: Introductionmentioning

confidence: 99%

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Stress-mediated convergence of splicing landscapes in male and female Rock Doves

Lang

MacManes

Calisi

et al. 2019

Preprint

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Background: The process of alternative splicing provides a unique mechanism by which eukaryotes are able to produce numerous protein products from the same gene. Heightened variability in the proteome has been thought to potentiate increased behavioral complexity and response flexibility to environmental stimuli, thus contributing to more refined traits on which natural and sexual selection can act. While it has been long known that various forms of environmental stress can negatively affect sexual behavior and reproduction, we know little of how stress can affect the alternative splicing associated with these events, and less still about how splicing may differ between sexes. Using the model of the rock dove (Columba livia), our team previously uncovered sexual dimorphism in the basal and stress-responsive gene transcription of a biological system necessary for facilitating sexual behavior and reproduction, the hypothlamic-pituitary-gonadal (HPG) axis. In this study, we delve further into understanding the mechanistic underpinnings of how changes in the environment can affect reproduction by testing the alternative splicing response of the HPG axis to an external stressor in both sexes.Results: This study reveals dramatic baseline differences in HPG alternative splicing between males and females. However, post submitting subjects to a restraint stress paradigm, we found a significant reduction in these differences between the sexes. In both stress and control treatments, we identified a higher incidence of splicing activity in the pituitary in both sexes as compared to other tissues. Of these splicing events, the core exon event is the most abundant form of splicing and more frequently occurs in the coding regions of the gene. Overall, we observed less splicing activity in the 3'UTR end of transcripts than the 5'UTR or coding regions. Conclusions:Our results provide vital new insight into sex-specific aspects of the stress response on the HPG axis at an unprecedented proximate level. Males and females uniquely respond to stress, yet exhibit splicing patterns suggesting a convergent, optimal splicing landscape for stress response. This information has the potential to inform evolutionary theory as well as the development of highly-specific drug targets for stress-induced reproductive dysfunction.

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Section: Convergent Landscape Hypothesissupporting

confidence: 81%

Section: Animal Collectionmentioning

confidence: 99%

Section: Animal Collectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stress-mediated convergence of splicing landscapes in male and female Rock Doves

Lang

MacManes

Calisi

et al. 2019

Preprint

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Effects of long‐term exposure to TDCPP in zebrafish (Danio rerio) – Alternations of hormone balance and gene transcriptions along hypothalamus‐pituitary axes

Liu

Hong

et al. 2022

Anim Models and Exp Med

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Background: TDCPP is one of the major chemical of organophosphate flame retardants (OPFRs) that has been detected ubiquitously in both the environment and biota. Previously we observed that it influenced the concentrations of sex and thyroid hormones in a sex-dependent pattern, leading to reproductive impairments after short-term exposure in zebrafish. Here we investigate the consequences of longerterm exposure to TDCPP on the hypothalamic-pituitary-gonad (HPG), hypothalamicpituitary-interrenal (HPI), and hypothalamic-pituitary-thyroid (HPT) axes of zebrafish (Danio rerio).Methods: A 120-day exposure test to 0.005, 0.05 and 0.5 mg/L TDCPP was initiated with fertilized eggs. Sex steroid hormones in the treated fishes were measured and transcriptional changes were analyzed. Results:In female fish, exposure to TDCPP resulted in increases in plasma cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), 17β-estradiol (E2), cortisol, thyroxine (T4), and triiodothyronine (T3). Transcription of most target genes along HPG, HPI and HPT axes were increased by the exposure. While in male fish the exposure led to decreases in cortisol, FSH, LH, T4, T3, testosterone (T), and 11-ketotestosterone (11-KT). Transcription of genes along HPG, HPI and HPT axes, especially steroidogenic genes, were inhibited in male zebrafish. While, E2/T or E2/11-KT ratio was increased in both female and females. The sex-dependent changes in hormones might be due to differential responses to TDCPP induced stresses. An increase in cortisol level coincided with increases in E2 and THs in female fish, while in males decreases in cortisol as well as T, 11-KT and THs were observed. Long-term exposure to TDCPP at very low (μg/L) concentrations could disrupt hormone balances in a sex dependent way. Conclusion:This study revealed that TDCPP could affect endocrine axes -HPG, HPI and HPT -in zebrafish, and impair zebrafish development.

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Hepatic Transcriptomic Responses to Ethinylestradiol in Two Life Stages of Japanese Quail

Jeon

Crump

Boulanger

et al. 2022

Enviro Toxic and Chemistry

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Chemical risk assessment for avian species typically depends on information from toxicity tests performed in adult birds. Early-life stage (ELS) toxicity tests have been proposed as an alternative, but incorporation of these data into existing frameworks will require knowledge about the similarities/differences between ELS and adult responses. The present study uses transcriptomics to assess hepatic gene expression in ELS and adult Japanese quail following exposure to ethinylestradiol (EE2). Prior to incubation, ELS quail were dosed with measured EE2 concentrations of 0.54, 6.3, and 54.2 µg/g egg weight via air cell injection. Adult quail were fed a single dose of EE2 at nominal concentrations of 0, 0.5, and 5 mg/kg body weight by gavage. Liver tissue was collected from five to six individuals per dose group at mid-incubation for ELS quail and 4 days after dosing for adults. A total of 283 and 111 differentially expressed genes (DEGs) were detected in ELS and adult quail, respectively, 16 of which were shared across life stages. Shared DEGs included estrogenic biomarkers such as vitellogenin genes and apovitellenin-1. For the dose groups that resulted in the highest number of DEGs (ELS, 6.3 µg/g; adult, 5 mg/kg), 21 and 35 Kyoto Encyclopedia of Genes and Genomes pathways were enriched, respectively. Ten of these pathways were shared between life stages, including pathways involved with signaling molecules and interaction and the endocrine system. Taken together, our results suggest conserved mechanisms of action following estrogenic exposure across two life stages, with evidence from differential expression of key biomarker genes and enriched pathways. The present study contributes to the development and evaluation of ELS tests and toxicogenomic approaches and highlights their combined potential for screening estrogenic chemicals.

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Widespread patterns of sexually dimorphic gene expression in an avian hypothalamic–pituitary–gonadal (HPG) axis

Cited by 12 publications

References 83 publications

Stress-mediated convergence of splicing landscapes in male and female Rock Doves

Stress-mediated convergence of splicing landscapes in male and female Rock Doves

Effects of long‐term exposure to TDCPP in zebrafish (Danio rerio) – Alternations of hormone balance and gene transcriptions along hypothalamus‐pituitary axes

Hepatic Transcriptomic Responses to Ethinylestradiol in Two Life Stages of Japanese Quail

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