Combining in vivo pathohistological and redox status analysis with in silico toxicogenomic study to explore the phthalates and bisphenol A mixture-induced testicular toxicity

Baralić, Katarina; Jorgovanović, Dragica; Živančević, Katarina; Djordjević, Aleksandra Buha; Miljaković, Evica Antonijević; Miljković, Milica; Kotur‐Stevuljević, Jelena; Antonijević, Biljana; Đukić-Ćosić, Danijela

doi:10.1016/j.chemosphere.2020.129296

Cited by 28 publications

(13 citation statements)

References 76 publications

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“…An insight into the intermediate products of lipid peroxidation and enzymes that generate these products could provide fruitful information for the present study. A similar mechanism of lipid peroxidation due to deleterious effects of reactive oxygen species on spermatozoa has been reported by Baralić et al [ 50 ] where MDA levels were increased after exposure to DBP, DEP, and bisphenol A. Increased NEFA concentrations were observed in DBP-10, whereas β -HB was increased in all the DBP-treated groups.…”

Section: Discussionsupporting

confidence: 80%

Effects of Subacute Exposure of Dibutyl Phthalate on the Homeostatic Model Assessment, Thyroid Function, and Redox Status in Rats

Majeed

Yousaf

Tahir

et al. 2021

BioMed Research International

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Dibutyl phthalate is an endocrine disruptor used in a wide range of industrial and agriculture applications. The present study focuses on elucidating the effect of subacute exposure (4-weeks) of DBP on insulin and its sensitivity indexes, oxidative status, thyroid function, energy metabolites, serum biochemistry, and anthropometry in rats. A total of 64 rats were divided into 4 treatment groups as mg DBP/Kg body weight per day: (a) 0 mg/Kg (control), (b) 10 mg/Kg (DBP-10), (c) 50 mg/Kg (DBP-50), and (d) 100 mg/Kg (DBP-100). The rats in each treatment ( n = 16 ) were further divided into male ( n = 8 ) and female ( n = 8 ) rats for studying treatment and gender interactions. Intraperitoneal glucose tolerance test (IPGTT) was performed on the 21st day. Anthropometry, nutritional determinants, fasting plasma glucose, fasting plasma insulin, homeostatic model assessment (HOMA), thyroid hormones, energy metabolites, and oxidative status were studied during the experimental period. Two-way ANOVA was used to analyze the data ( p < 0.05 ). Tukey’s posthoc test was used for pair-wise comparisons. DBP increased body weight gain and feed efficiency in an inverted nonmonotonic U -shaped fashion. Hyperglycemia and increased blood glucose area under the curve were observed in DBP-100 at 120 minutes in IPGTT. The HOMA also showed a linear monotonic contrast. Thyroxin decreased significantly in the DBP-100 rats, whereas malondialdehyde, nonesterified fatty acids, and beta hydroxyl butyrate were increased with the DBP treatments. In conclusion, DBP could be attributed to the development of hyperglycemia and insulin resistance in rats. Further investigations into the lipid peroxidation pathways can improve our understanding of the mechanisms involved in metabolic disruption.

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Section: Discussionsupporting

confidence: 80%

Effects of Subacute Exposure of Dibutyl Phthalate on the Homeostatic Model Assessment, Thyroid Function, and Redox Status in Rats

Majeed

Yousaf

Tahir

et al. 2021

BioMed Research International

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“…In the male reproductive system, BPA and DEHP administered in binary mixtures always showed antagonistic scores for all the significantly altered endpoints ( Table 4 ), and this feature can account for the lack of correlation between effects due to exposure to single compounds and the mixtures. Male rats treated per os with DEHP (50 mg/kg bw/day), DBP (50 mg/kg bw/day), BPA (25 mg/kg bw/day) and their MIX (50 mg/kg bw/day DEHP + 50 mg/kg bw/day DBP + 25 mg/kg bw/day BPA) showed more evident testicular toxicity in the MIX group (desquamated germinal epithelium cells, enlarged cells with hyperchromatic nuclei, multinucleated cells and intracytoplasmic vacuoles) in comparison with the individual chemicals, while effects on redox status were either more prominent, or present only in the MIX group, confirming that the male reproductive system might be more susceptible following exposure to chemicals in mixtures than individually [ 38 ]. Moreover, when orally administered during pregnancy and lactation, the mixture of BPA (50 mg/kg/day), DEHP (30 mg/kg/day) and their binary mixture (50 mg/kg/day BPA + 30 mg/kg/day DEHP) shows more dramatic changes in both testicular structure and cell death [ 39 ].…”

Section: Discussionmentioning

confidence: 97%

Toxicological Assessment of Oral Co-Exposure to Bisphenol A (BPA) and Bis(2-ethylhexyl) Phthalate (DEHP) in Juvenile Rats at Environmentally Relevant Dose Levels: Evaluation of the Synergic, Additive or Antagonistic Effects

Tassinari

Tait

Busani

et al. 2021

IJERPH

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Background: The general population (including children) is exposed to chemical mixtures. Plasticizers such as Bisphenol A (BPA) and Phthalates (mainly Bis(2-ethylhexyl) phthalate-DEHP) are widespread contaminants classified as endocrine disrupters which share some toxicological profiles and coexist in food and environment. Methods: To identify hazards of DEHP and BPA mixtures, the juvenile toxicity test—where rodents are in peripubertal phase of development, resembling childhood—was selected using exposure data from biomonitoring study in children. Biological activity and potential enhanced and/or reduced toxicological effects of mixtures due to common mechanisms were studied, considering endpoints of metabolic, endocrine and reproductive systems. The degree of synergy or antagonism was evaluated by synergy score calculation, using present data and results from the single compound individually administered. Results: In metabolic system, synergic interaction predominates in female and additive in male rats; in the reproductive and endocrine systems, the co-exposure of BPA and DEHP showed interactions mainly of antagonism type. Conclusions: The present approach allows to evaluate, for all the endpoints considered, the type of interaction between contaminants relevant for human health. Although the mode of action and biological activities of the mixtures are not completely addressed, it can be of paramount usefulness to support a more reliable risk assessment.

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“…Mechanistically, BPA and NP could disrupt the expression of early-meiotic germ cell marker genes and were considered to have a feminizing effect that might be implicated in suppressing male gonadal development (Tanaka et al, 2019). Furthermore, the common exposure to BPA and other EEDs, such as di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), synergistically disturbed the hormone metabolism to induce testicular toxicity and the occurrence of reproductive dysfunction (Balcı et al, 2020; Baralić et al, 2021). This may also be ascribed to the interaction of the mentioned chemicals and they would magnify one another’s effects (Pollock et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

BPA-induced prostatic hyperplasia in vitro is correlated with the unbalanced gene expression of AR and ER in the epithelium and stroma

et al. 2021

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As a typical environmental endocrine disruptor (EED), bisphenol A (BPA) can induce pathological hyperplasia of the prostatic epithelium and stroma. This study concentrates mainly on the effect and underlying mechanisms of BPA on prostatic hyperplasia, which is based on the culture of primary human prostate epithelial cells (HPEpiC) and human prostate fibroblasts (HPrF). In an effect to screen the optimal pro-survival BPA levels, HPEpiC and HPrF were, respectively, exposed to concentration gradients of BPA (10−12 M–10−4 M) solution diluted with two corresponding medium and incubated for 72 h at 37°C. CCK-8 assay showed that 10−9 M–10−5 M BPA could facilitate the proliferation of HPEpiC, while similar proliferative effect of HPrF only needed 10−11 M–10−7 M BPA. HPrF were more sensitive to BPA than HPEpiC. The qualification of PCNA gene expression measured using quantitative real-time polymerase chain reaction (qRT-PCR) also mirrored the BPA-induced cell proliferation. Additionally, our results considered that androgen receptor (AR), estrogen receptor (ERα, ERβ), and NFKB1 gene expressions exhibited up-regulation in HPEpiC treated with 10−9 M BPA for 72 h. However, in HPrF, the identical BPA treatment could activate ERα, ERβ, and NFKB1 gene expressions and down-regulated the expression of AR levels. It is further confirmed that low-dose BPA can indeed promote the proliferation of human prostate cells in vitro, and the mechanisms of BPA for prostatic epithelial and stromal hyperplasia may not be consistent.

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Combining in vivo pathohistological and redox status analysis with in silico toxicogenomic study to explore the phthalates and bisphenol A mixture-induced testicular toxicity

Cited by 28 publications

References 76 publications

Effects of Subacute Exposure of Dibutyl Phthalate on the Homeostatic Model Assessment, Thyroid Function, and Redox Status in Rats

Effects of Subacute Exposure of Dibutyl Phthalate on the Homeostatic Model Assessment, Thyroid Function, and Redox Status in Rats

Toxicological Assessment of Oral Co-Exposure to Bisphenol A (BPA) and Bis(2-ethylhexyl) Phthalate (DEHP) in Juvenile Rats at Environmentally Relevant Dose Levels: Evaluation of the Synergic, Additive or Antagonistic Effects

BPA-induced prostatic hyperplasia in vitro is correlated with the unbalanced gene expression of AR and ER in the epithelium and stroma

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