Abstract A47: PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland

Abstract

Abstract Background: Perfluorooctanoic acid (PFOA) and zeranol (Zer) are known as endocrine-disrupting chemicals (EDCs); however, their potential either alone or in combination of increasing the susceptibility to breast cancer is still not fully understood. Here, we hypothesize that pubertal exposure to these EDCs has an impact on the transcriptomic profile of the mammary glands, which explains the less differentiated phenotype and increased susceptibility to carcinogenesis when challenged with a chemical carcinogens like DMBA. Methods: Female Sprague-Dawley rats at 21 days of age were assigned to four groups and received daily gavage for three weeks with PFOA and Zer alone or in combination. A control group received only sesame oil. At 50 days and 100 days of age (d50 and d100, respectively) the animals were euthanized and the mammary glands were collected, the RNA was extracted, and a RNA-seq library was constructed and sequenced. Results: We detected differentially expressed genes (DEGs, absolute fold change > 2 and FDR p< 0.05) at d50 by PFOA 136 (106 up- and 30 downregulated), Zer 394 (370 up and 24 down), and PFOA+Zer 630 (244 up and 386 down); and at d100, PFOA 74 DEGs (23 up and 51 down), Zer 405 (11 up and 394 down), and PFOA+Zer 669 (98 up and 571 down). Zer and PFOA+Zer caused the remarkable number of genes with expression alteration at both of two endpoints. Gene ontology enrichment analyses revealed that zeranol affects immune response at d50 but is majorly associated with tissue development at d100, whereas PFOA affects cell development at d50 but is mainly related to morphogenesis at d100. Meanwhile, PFOA+Zer is associated with metabolic process at both of two endpoints. KEGG pathway analysis demonstrated that PFOA+Zer’s effects at both d50 and d100 were notably mediated through PI3K-Akt and PPAR signaling pathways. Conclusion: A relevant and significant finding is that each compound induces a different transcriptomic profile and changes its biologic effects between day 50 and day 100 of age, and when both compounds are administered together the transcriptomic profile differs from that induced by each individual one. The major EDCs affected pathways are PI3K-Akt and PPAR signaling, indicating that the long-term damaging effect of the combination of EDCs explains the less differentiated phenotype and its higher susceptibility to develop mammary cancer when challenged with a chemical carcinogen. (This work was supported by the NIEHS/NCI grant U01ES026130 and NCI/NIH Cancer Center Support Grant P30-CA006927.) Citation Format: Nhi M. Dang, Yanrong Su, Julia Santucci-Pereira, Jose Russo. PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A47.