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Effects of Pubertal Exposure to Butyl Benzyl Phthalate, Perfluorooctanoic Acid, and Zeranol on Mammary Gland Development and Tumorigenesis in Rats

1
The Irma H Russo, MD-Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
2
Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA 02460, USA
3
Pioneer Valley Life Sciences Institute, UMASS Chan Medical School-Baystate, Springfield, MA 01199, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Dr. Russo passed away on 24 September 2021.
Academic Editors: Karel Smetana, Jr. and Michal Kolář
Int. J. Mol. Sci. 2022, 23(3), 1398; https://doi.org/10.3390/ijms23031398
Received: 22 December 2021 / Revised: 18 January 2022 / Accepted: 24 January 2022 / Published: 26 January 2022
(This article belongs to the Special Issue Molecular Signal Transduction in Tumor Progression and Metastasis)
Endocrine-disrupting chemicals (EDCs)—including butyl benzyl phthalate (BBP), perfluorooctanoic acid (PFOA), and zeranol (α-ZAL, referred to as ZAL hereafter)—can interfere with the endocrine system and produce adverse effects. It remains unclear whether pubertal exposure to low doses of BBP, PFOA, and ZAL has an impact on breast development and tumorigenesis. We exposed female Sprague Dawley rats to BBP, PFOA, or ZAL through gavage for 21 days, starting on day 21, and analyzed their endocrine organs, serum hormones, mammary glands, and transcriptomic profiles of the mammary glands at days 50 and 100. We also conducted a tumorigenesis study for rats treated with PFOA and ZAL using a 7,12-dimethylbenz[a]anthracene (DMBA) model. Our results demonstrated that pubertal exposure to BBP, PFOA, and ZAL affected endocrine organs and serum hormones, and induced phenotypic and transcriptomic changes. The exposure to PFOA + ZAL induced the most phenotypic and transcriptomic changes in the mammary gland. PFOA + ZAL downregulated the expression of genes related to development at day 50, whereas it upregulated genes associated with tumorigenesis at day 100. PFOA + ZAL exposure also decreased rat mammary tumor latency, reduced the overall survival of rats after DMBA challenge, and affected the histopathology of mammary tumors. Therefore, our study suggests that exposure to low doses of EDCs during the pubertal period could induce changes in the endocrine system and mammary gland development in rats. The inhibition of mammary gland development by PFOA + ZAL might increase the risk of developing mammary tumors through activation of signaling pathways associated with tumorigenesis. View Full-Text
Keywords: endocrine-disrupting chemicals; pubertal exposure; mammary gland development; tumorigenesis; RNA sequencing; estrogen signaling; Wnt signaling endocrine-disrupting chemicals; pubertal exposure; mammary gland development; tumorigenesis; RNA sequencing; estrogen signaling; Wnt signaling
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MDPI and ACS Style

Su, Y.; Santucci-Pereira, J.; Dang, N.M.; Kanefsky, J.; Rahulkannan, V.; Hillegass, M.; Joshi, S.; Gurdogan, H.; Chen, Z.; Bessonneau, V.; Rudel, R.; Ser-Dolansky, J.; Schneider, S.S.; Russo, J. Effects of Pubertal Exposure to Butyl Benzyl Phthalate, Perfluorooctanoic Acid, and Zeranol on Mammary Gland Development and Tumorigenesis in Rats. Int. J. Mol. Sci. 2022, 23, 1398. https://doi.org/10.3390/ijms23031398

AMA Style

Su Y, Santucci-Pereira J, Dang NM, Kanefsky J, Rahulkannan V, Hillegass M, Joshi S, Gurdogan H, Chen Z, Bessonneau V, Rudel R, Ser-Dolansky J, Schneider SS, Russo J. Effects of Pubertal Exposure to Butyl Benzyl Phthalate, Perfluorooctanoic Acid, and Zeranol on Mammary Gland Development and Tumorigenesis in Rats. International Journal of Molecular Sciences. 2022; 23(3):1398. https://doi.org/10.3390/ijms23031398

Chicago/Turabian Style

Su, Yanrong, Julia Santucci-Pereira, Nhi M. Dang, Joice Kanefsky, Vishnuprabha Rahulkannan, Meardey Hillegass, Shalina Joshi, Hafsa Gurdogan, Zhen Chen, Vincent Bessonneau, Ruthann Rudel, Jennifer Ser-Dolansky, Sallie S. Schneider, and Jose Russo. 2022. "Effects of Pubertal Exposure to Butyl Benzyl Phthalate, Perfluorooctanoic Acid, and Zeranol on Mammary Gland Development and Tumorigenesis in Rats" International Journal of Molecular Sciences 23, no. 3: 1398. https://doi.org/10.3390/ijms23031398

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