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. 2025 Apr 1:599:112460.
doi: 10.1016/j.mce.2025.112460. Epub 2025 Jan 9.

Transcriptomic analysis of effects of developmental PCB exposure in the hypothalamus of female rats

Affiliations

Transcriptomic analysis of effects of developmental PCB exposure in the hypothalamus of female rats

Madeline Streifer et al. Mol Cell Endocrinol. .

Abstract

This study investigated the consequences of perinatal exposure to Aroclor 1221 (A1221), a weakly estrogenic polychlorinated biphenyl (PCB) mixture and known endocrine-disrupting chemical (EDC), in female rats. Previous work has shown behavioral and physiological effects of A1221, and the current study extended this work to comprehensive transcriptomic profiling of two hypothalamic regions involved in the control of reproduction: the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). Female Sprague-Dawley rats were fed a cookie treated with a small volume of A1221 (1 mg/kg) or vehicle (3% DMSO in sesame oil) during pregnancy from gestational days 8-18 and after birth from postnatal (P) days 1-21, exposing the offspring via placental and lactational transfer. In female offspring, developmental, physiological, and hormonal effects of A1221 were relatively modest. However, because prior work has implicated this exposure in neurobehavioral disruptions, we sought to determine whether developmental programming of the brain transcriptome could underlie these latter phenotypes. We used 3' targeted RNA sequencing in the hypothalamus (arcuate nucleus, anteroventral periventricular nucleus) of experimental females at P8, 30, and 60 and identified significant alterations in gene expression and gene ontology (GO) terms in an age- and tissue-specific manner. Most notably, terms related to synaptic signaling, neurotransmitter regulation, immune response, and cellular structure were identified. Changes in pathways associated with synaptic functions and cellular metabolism were further identified, indicating that A1221 exposure can impact neurodevelopmental and neuroendocrine processes at a molecular level, even in the absence of overt developmental changes. These findings of molecular reprogramming may explain the behavioral effects of A1221 and highlight novel molecular targets and pathways that warrant further investigation to understand the effects of EDCs on the developing brain.

Keywords: Anteroventral periventricular nucleus (AVPV); Arcuate nucleus (ARC); Aroclor 1221; Endocrine-disrupting chemical (EDC); PCB; Transcriptomics.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrea C Gore reports financial support was provided by National Institute of Environmental Health Sciences. Andrea C Gore reports a relationship with Endocrine Society that includes: board membership. Andrea C Gore reports a relationship with Friedman Rubin LLC that includes: paid expert testimony. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Body weight (A - C) and anogenital index (D) are shown as mean ± SEM. A. Body weight was significantly higher in A1221 than in vehicle female rats in the postnatal period at P14 (p = 0.006). Adolescent (B) and adult (C) body weight, and anogenital index (D), were unaffected by treatment. Both body weight and AGI increased significantly with each increasing age point (p < 0.0001). Postnatal body weight and anogenital index: n = 18 vehicle, n = 16 A1221; adolescent body weight: n = 9 vehicle, n = 8 A1221; adult body weight: n = 9 vehicle, n = 8 A1221.
Fig. 2.
Fig. 2.
Age at vaginal opening (VO) is shown as mean ± SEM. Although A1221 females underwent puberty a half day later (35.6 for A1221, 35.0 for vehicle) this was not a significant difference. N = 9 vehicle, n = 8 A1221.
Fig. 3.
Fig. 3.
Serum hormone concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol are shown as mean ± SEM. A. P8 females had significantly higher concentrations of FSH than P30 (p < 0.0001) and P60 (p < 0.0001) females. A1221 decreased serum FSH at P8 (p = 0.044). FSH concentrations at P30 and P60 were unaffected by treatment. B. LH was not significantly affected by treatment and age. C. A1221 had no effects on serum estradiol concentrations. Estradiol was significantly affected by age: compared to P30, estradiol was higher at P8 (p = 0.019) and P60 (p = 0.037). FSH and LH at P8, P30, and P60: n = 6, 9, and 8 vehicle, n = 6, 7, and 8 A1221; estradiol: n = 5, 9, and 9 vehicle, n = 6, 8, and 8 A1221.
Fig. 4.
Fig. 4.
Boxplots showing the distribution of TMM-normalized gene expression counts across samples for significantly different genes. Each box represents the interquartile range (IQR) of expression values, with the median indicated by the central line, and whiskers extending to 1.5 times the IQR. Dark points outside the whiskers exceed the 1.5 IQR, light points are individual expression levels. A. At P30, female rats with perinatal A1221 exposure had significantly higher expression of the kisspeptin receptor gene Kissr1 relative to Vehicle controls in the arcuate nucleus (ARC) of the hypothalamus. * = p = 0.02. B. At P60, A1221 significantly reduced Kiss1r expression relative to Vehicle controls in the ARC. * = p = 0.05. C. At P60, A1221 significantly increased expression of the tachykinin-3 protein encoding gene Tac3 compared to Vehicle controls in the anteroventral periventricular nucleus (AVPV).
Fig. 5.
Fig. 5.
Transcriptomic analysis. Volcano plots show −log10 eFDR adjusted p-value of differentially expressed genes (DEGs) between vehicle and A1221-exposed rats. Vertical lines represent 1x fold change in gene expression. DEGs are denoted by color, with orange indicating downregulation and blue indicating upregulation in A1221 when compared to vehicle exposed rats. (A – E). Labeled DEGs are described in Table 4.
Fig. 6.
Fig. 6.
Significantly enriched GO terms are shown. From the top 25 most significantly impacted biological processes GO terms in each region, 10 were selected for their roles in neurological function. The specific GO terms are shown on the Y axis for each region, with the number of constituent genes comprising the GO term shown on the X axis. The size of the points indicates the relative magnitude (−log10 of FDR) of significance. Effects are for A1221 relative to vehicle controls.

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References

    1. Andreu-Cervera A, Catala M, Schneider-Maunoury S, 2021. Cilia, ciliopathies and hedgehog-related forebrain developmental disorders. Neurobiol. Dis. 150, 105236. 10.1016/j.nbd.2020.105236. - DOI - PubMed
    1. Andrews S, 2015. A quality control tool for high throughput sequence data. Available online: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/.
    1. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G, 2000. Gene ontology: tool for the unification of biology. Nat. Genet 25 (1), 25–29. 10.1038/75556. - DOI - PMC - PubMed
    1. Bartzen-Sprauer J, Klosen P, Ciofi P, Mikkelsen JD, Simonneaux V, 2014. Photoperiodic co-regulation of kisseptin, neurokinin B and dynorphin in the hypothalamus of a seasonal rodent. J. Neuroendocrinol. 26 (8), 510–520. 10.1111/jne.12171. - DOI - PubMed
    1. Bell MR, 2018. Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans. Endocrinology 159 (7), 2596–2613. 10.1210/en.2018-00220. - DOI - PMC - PubMed

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