Di-n-Butyl Phthalate and Its Monoester Metabolite Impairs Steroid Hormone Biosynthesis in Human Cells: Mechanistic In Vitro Studies

Källsten, Liselott; Pierozan, Paula; Martin, Jonathan W.; Karlsson, Oskar

doi:10.3390/cells11193029

Cited by 10 publications

(8 citation statements)

References 42 publications

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“…phthalates [60][61][62], bisphenols [63,64], PFAS, or PCBs [48]. In silico analyses demonstrated direct inhibitory effects of phthalates on CYP450 enzymes involved in steroidogenesis via molecular docking.…”

Section: Steroidogenic Enzyme Expressionmentioning

confidence: 99%

“…Phthalates Diethlyhexylphthalate (DEHP),Dibutylphthalate (DBP) DEHP Plasticizesr in polyvinyl chloride polymers (PVC); found in wires, plastic bottles, medical equipment, lacquers, varnishes, paints, fixatives in perfumes, insect repellents Androgen, glucocorticoid, progestogen activity [43]; PPARγ affinity [46]; disrupted expression of potassium channels [49], AGTR1a/b, LDL-R [50]; differentially activated transcription factors [54]; ↑ DNA methylation [44]; cholesterol synthesis [50]; disrupted expression of StAR, CYP, HSD [60][61][62];…”

Section: Bisphenolsmentioning

confidence: 99%

“…CYP-inhibiting effects [65]; binding of CBG, SHBG [77,78], human serum albumin [81]; ↑ ROS, gene and protein oxidation [60]; Iipid accumulation [50];…”

Section: Bisphenolsmentioning

confidence: 99%

“…In H295R cell culture, superoxide gene and protein oxidation were induced in the presence of di-/ monobutyl phthalate (DBP/MBP), while gene expression of essential CYP enzymes was decreased. Consequently, DBP treatment led to lowered androgen and corticosterone secretion [60].…”

Section: Oxidative Stressmentioning

confidence: 99%

“…disrupted gene expression of StAR [58], CYP, HSD [63,64]; ↓ antioxidant defence, ↑ ROS [36]; ↑ serum glucocorticoids (GC) [74,75]; ↓ GR expression [75]; vascular congestion [36]; ↑ ZF thickness, ↓ ZR thickness [75]; less robust coping to stressors, sex-dependent neurobehavioral alterations (anxiety, depression-like phenotype) [73][74] Phthalates Diethlyhexyl-phthalate (DEHP), Dibutyl-phthalate (DBP) DEHP Plasticizers in polyvinyl chloride polymers (PVC); found in wires, plastic bottles, medical equipment, lacquers, varnishes, paints, fixatives in perfumes, insect repellents Androgen, glucocorticoid, progestogen activity [43]; PPARγ affinity [46]; disrupted expression of potassium channels [49], AGTR1a/b, LDL-R [50]; differentially activated transcription factors [54]; ↑ DNA methylation [44]; cholesterol synthesis [50]; disrupted expression of StAR, CYP, HSD [60][61][62]; CYP-inhibiting effects [65]; binding of CBG, SHBG [77,78], human serum albumin [81]; ↑ ROS, gene and protein oxidation [60]; lipid accumulation [50];…”

Section: Receptor Expressionmentioning

confidence: 99%

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Endocrine Disruptors: Focus on the Adrenal Cortex

Pötzl,

Kürzinger,

Stopper

et al. 2023

Horm Metab Res

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Endocrine-disrupting chemicals (EDCs) are exogenous substances known to interfere with endocrine homeostasis and promote adverse health outcomes. Their impact on the adrenal cortex, corticosteroids and their physiological role in the organism has not yet been sufficiently elucidated. In this review, we collect experimental and epidemiological evidence on adrenal disruption by relevant endocrine disruptors. In vitro data suggest significant alterations of gene expression, cell signalling, steroid production, steroid distribution, and action. Additionally, morphological studies revealed disturbances in tissue organization and development, local inflammation, and zone-specific hyperplasia. Finally, endocrine circuits, such as the hypothalamic-pituitary-adrenal axis, might be affected by EDCs. Many questions regarding the detection of steroidogenesis disruption and the effects of combined toxicity remain unanswered. Not only due to the diverse mode of action of adrenal steroids and their implication in many common diseases, there is no doubt that further research on endocrine disruption of the adrenocortical system is needed.

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Section: Steroidogenic Enzyme Expressionmentioning

confidence: 99%

Section: Bisphenolsmentioning

confidence: 99%

“…CYP-inhibiting effects [65]; binding of CBG, SHBG [77,78], human serum albumin [81]; ↑ ROS, gene and protein oxidation [60]; Iipid accumulation [50];…”

Section: Bisphenolsmentioning

confidence: 99%

Section: Oxidative Stressmentioning

confidence: 99%

Section: Receptor Expressionmentioning

confidence: 99%

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Endocrine Disruptors: Focus on the Adrenal Cortex

Pötzl,

Kürzinger,

Stopper

et al. 2023

Horm Metab Res

View full text Add to dashboard Cite

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Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations

Almamoun,

Pierozan,

Karlsson

2024

Arch Toxicol

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To improve the mechanistic screening of reproductive toxicants in chemical-risk assessment and drug development, we have developed a three-dimensional (3D) heterogenous testicular co-culture model from neonatal mice. Di-n-butyl phthalate (DBP), an environmental contaminant that can affect reproductive health negatively, was used as a model compound to illustrate the utility of the in vitro model. The cells were treated with DBP (1 nM to 100 µM) for 7 days. Automated high-content imaging confirmed the presence of cell-specific markers of Leydig cells (CYP11A1 +), Sertoli cells (SOX9 +), and germ cells (DAZL +). Steroidogenic activity of Leydig cells was demonstrated by analyzing testosterone levels in the culture medium. DBP induced a concentration-dependent reduction in testosterone levels and decreased the number of Leydig cells compared to vehicle control. The levels of steroidogenic regulator StAR and the steroidogenic enzyme CYP11A1 were decreased already at the lowest DBP concentration (1 nM), demonstrating upstream effects in the testosterone biosynthesis pathway. Furthermore, exposure to 10 nM DBP decreased the levels of the germ cell-specific RNA binding protein DAZL, central for the spermatogenesis. The 3D model also captured the development of the Sertoli cell junction proteins, N-cadherin and Zonula occludens protein 1 (ZO-1), critical for the blood–testis barrier. However, DBP exposure did not significantly alter the cadherin and ZO-1 levels. Altogether, this 3D in vitro system models testicular cellular signaling and function, making it a powerful tool for mechanistic screening of developmental testicular toxicity. This can open a new avenue for high throughput screening of chemically-induced reproductive toxicity during sensitive developmental phases.

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Screening persistent organic pollutants for effects on testosterone and estrogen synthesis at human-relevant concentrations using H295R cells in 96-well plates

Strand,

Nylander,

Höglund

et al. 2024

Cell Biol Toxicol

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Many persistent organic pollutants (POPs) are suspected endocrine disruptors and it is important to investigate their effects at low concentrations relevant to human exposure. Here, the OECD test guideline #456 steroidogenesis assay was downscaled to a 96-well microplate format to screen 24 POPs for their effects on viability, and testosterone and estradiol synthesis using the human adrenocortical cell line H295R. The compounds (six polyfluoroalkyl substances, five organochlorine pesticides, ten polychlorinated biphenyls and three polybrominated diphenyl ethers) were tested at human-relevant levels (1 nM to 10 µM). Increased estradiol synthesis, above the OECD guideline threshold of 1.5-fold solvent control, was shown after exposure to 10 µM PCB-156 (153%) and PCB-180 (196%). Interestingly, the base hormone synthesis varied depending on the cell batch. An alternative data analysis using a linear mixed-effects model that include multiple independent experiments and considers batch-dependent variation was therefore applied. This approach revealed small but statistically significant effects on estradiol or testosterone synthesis for 17 compounds. Increased testosterone levels were demonstrated even at 1 nM for PCB-74 (18%), PCB-99 (29%), PCB-118 (16%), PCB-138 (19%), PCB-180 (22%), and PBDE-153 (21%). The MTT assay revealed significant effects on cell viability after exposure to 1 nM of perfluoroundecanoic acid (12%), 3 nM PBDE-153 (9%), and 10 µM of PCB-156 (6%). This shows that some POPs can interfere with endocrine signaling at concentrations found in human blood, highlighting the need for further investigation into the toxicological mechanisms of POPs and their mixtures at low concentrations relevant to human exposure. Graphical Abstract

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Di-n-Butyl Phthalate and Its Monoester Metabolite Impairs Steroid Hormone Biosynthesis in Human Cells: Mechanistic In Vitro Studies

Cited by 10 publications

References 42 publications

Endocrine Disruptors: Focus on the Adrenal Cortex

Endocrine Disruptors: Focus on the Adrenal Cortex

Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations

Screening persistent organic pollutants for effects on testosterone and estrogen synthesis at human-relevant concentrations using H295R cells in 96-well plates

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