Background: Myocardial fibrosis is a critical pathological basis for the poor prognosis of cardiovascular diseases. Studies have found that myocardial fibrosis is closely associated with exposure to environmental estrogens such as nonylphenol (NP), as a representative of environmental estrogens. The aim of this study was to examine the effects of NP chronic exposure on myocardial fibrosis as well as cardiac structure and function. Forty Sprague Dawley rats were randomly divided into four groups (n = 10): control group (C), low NP dose (0.4 mg/kg, L), medium NP dose (4 mg/kg, M), and high NP dose (40 mg/kg, H) groups. The NP dose groups were gavaged with NP for 180 days. Results: The NP level in the heart of the NP groups was significantly higher than those in the control group (F = 43.658, P < 0.001). Serum aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase isozyme (CK-MB), lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) significantly increased in the NP groups compared with the control group (). Histopathological examination of the heart biopsy illustrates that in the medium and high NP groups, the fibrous connective tissue had a disordered and loose gridding shape, muscle fibers had fractured, and muscle fibers were loose with a widened gap. Extensive inflammatory cell infiltration and fibroblast proliferation in the myocardial interstitium were also found. With increasing NP dose, the degree of muscle fiber loosing and disorder became more significant in the NP treatment groups, and the collagen volume fraction (CVF) was higher than that in the control group (P < 0.01). Compared with the control group, the expression of collagen I and collagen III increased significantly in the medium and high NP groups (P < 0.05). The values of the systolic thickness of the left ventricular anterior wall (LVAWs), the diastolic thickness of the left ventricular posterior wall (LVPWd), the systolic thickness of the left ventricular posterior wall (LVPWs), and the left ventricular anterior wall (LVAWd) in the NP groups are were slightly lower than those in of the control group. The values of left ventricular end systolic dimensions (LVIDs) in the NP groups increased compared with the control group. Conclusions: Long-term NP exposure could lead to fibrosis in the rat myocardium, which is characterized by increased expressions of myocardial collagen I and collagen III, as well as elevated cardiac enzymes. In addition, the cardiac structure was affected and changes were observed in the thinner ventricular wall and as an enlarged ventricular cavity.

Background Previous studies have shown that EDCs may activate nuclear transcription factor, such as activator protein-1 (AP-1), nuclear factor of activated Tcells (NF-AT) and nuclear factor kappa B (NF-κB) in the process of immune damage. At the same time, some experts believed that estrogen may play an important role in this process. As a typical representative of EDCs, nonylphenol (NP) has not been reported. The aim of this work was to explore the relationship between the immune inflammatory damage and the changes in estrogen expression in male rats during the chronic exposure to NP at environmental concentrations. Sixty SPF Sprague–Dawley rats were divided into five groups (n = 12 per group): blank control group (corn oil), low-dose NP exposure group (0.4 mg/kg/d), medium-dose NP exposure group (4 mg/kg/d), high-dose NP exposure group (40 mg/kg/d), and estradiol control group (E2: 30 μg/kg/d). Results Compared with the control group, rat spleen organ coefficient, number of spleen nodules, relative area of lymph nodes and white pulp were relatively reduced in the L (NP, 0.4 mg/kg) and H (NP, 40 mg/kg) exposure dose groups (P < 0.001). Lymphocytes were rich in cytoplasm, mitochondria were swollen, part of the cristae was reduced, and rough endoplasmic reticulum was expanded. The serum levels of IgG (P < 0.001) and IgM (P = 0.002) showed a downward trend. The percentage of Th cells (CD3+CD4+) was significantly decreased (P < 0.001), and the percentage of B lymphocytes shows an opposite trend (P < 0.001). Giemsa staining showed that the number of neutrophils (P < 0.001) was increased. The expressions of estrogen receptor ER-α and ER-β protein in the spleen increased significantly (P < 0.001). The expressions of AP-1 protein and NF-AT protein in the spleen were increased, and the expression of NF-KB protein was decreased (P < 0.001). The expressions of IL-4, ER-α and ER-β (P < 0.001) levels in serum increased. The mRNA-seq bioinformatics detection showed the final differentially expressed immune-inflammatory-related genes between the control and H-NP groups as follow: down-regulated: TLR4, Gata3, IL12, up-regulated: TNF-a, IL10, INOS. The mRNA expressions of ER-α, ER-β, NF-KB, IL4, AP-1, TLR4, Gata3, and NF-AT were consistent with the results of mRNA-seq analysis. NP content was correlated with the expressions of ER-α, ER-β, IL4, AP-1, NF-AT, TLR4, NF-KB, as well as IL-12 proteins in the spleen tissue ([r] < 1, P < 0.05). Conclusions Chronic exposure to NP at environmental concentration could cause immune dysfunction, resulting in immunotoxicity and inflammatory effects, and lead to changes in the activity of transcription factors and differential immune inflammatory factors in rats. Graphical Abstract

Background Myocardial fibrosis is a critical pathological basis for the poor prognosis of cardiovascular diseases. Studies have found that myocardial fibrosis is closely associated with exposure to environmental estrogens such as nonylphenol (NP), as a representative of environmental estrogens. The aim of this study was to examine the effects of NP chronic exposure on myocardial fibrosis as well as cardiac structure and function. Forty Sprague–Dawley rats were randomly divided into four groups (n = 10): control group (C), low NP dose (0.4 mg/kg, L), medium NP dose (4 mg/kg, M), and high NP dose (40 mg/kg, H) groups. The NP dose groups were gavaged with NP for 180 days. Results The NP level in the heart of the NP groups was significantly higher than those in the control group (F = 43.658, P < 0.001). Serum aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase isozyme (CK-MB), lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) significantly increased in the NP groups compared with the control group (P < 0.05). Histopathological examination of the heart biopsy illustrates that in the medium and high NP groups, the fibrous connective tissue had a disordered and loose gridding shape, muscle fibers had fractured, and muscle fibers were loose with a widened gap. Extensive inflammatory cell infiltration and fibroblast proliferation in the myocardial interstitium were also found. With increasing NP dose, the degree of muscle fiber loosing and disorder became more significant in the NP-treatment groups, and the collagen volume fraction (CVF) was higher than that in the control group (P < 0.01). Compared with the control group, the expression of collagen I and collagen III increased significantly in the medium and high NP groups (P < 0.05). The values of the systolic thickness of the left ventricular anterior wall (LVAWs), the diastolic thickness of the left ventricular posterior wall (LVPWd), the systolic thickness of the left ventricular posterior wall (LVPWs), and the left ventricular anterior wall (LVAWd) in the NP groups are were slightly lower than those in of the control group. The values of left ventricular end systolic dimensions (LVIDs) in the NP groups increased compared with the control group. Conclusions Long-term NP exposure could lead to fibrosis in the rat myocardium, which is characterized by increased expressions of myocardial collagen I and collagen III, as well as elevated cardiac enzymes. In addition, the cardiac structure was affected and changes were observed in the thinner ventricular wall and as an enlarged ventricular cavity.

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