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Perfluoroalkylated carboxylic acids (PFCAs) are a subclass of man-made chemicals that have been widely used in industrial production and consumer products. As a result, PFCAs have been found to accumulate in the environment and bioaccumulate in organisms, leading to potential health and environmental impacts. This study investigated the inhibition of 11 PFCAs on gonadal 3β-hydroxysteroid dehydrogenases in humans, rats, and mice. We observed a V-shaped inhibition pattern against human granulosa (KGN) cell 3β-HSD2 starting from C9 (half-maximal inhibitory concentration, IC 50 , 100.8 μM) to C11 (8.92 μM), with a V-shaped turn. The same V-shaped inhibition pattern was also observed for PFCAs against rat testicular 3β-HSD1 from C9 (IC 50 , 50.43 μM) to C11 (6.60 μM). Mouse gonadal 3β-HSD6 was insensitive to the inhibition of PFCAs, with an IC 50 of 50.43 μM for C11. All of these PFCAs were mixed inhibitors of gonadal 3β-HSDs. Docking analysis showed that PFCAs bind to the nicotinamide adenine dinucleotide (NAD+)/steroid binding sites of these enzymes and bivariate correlation analysis showed that molecular length determines the inhibitory pattern of PFCAs on these enzymes. In conclusion, the carbon chain length determines the inhibitory strength of PFCAs on human, rat, and mouse gonadal 3β-HSDs, and the inhibitory strength of PFCAs against human and rat 3β-HSD enzymes shows V-shaped turn. [Display omitted] • PFAS inhibit human and rat 3β-HSDs. • The potency of perfluoroalkyl carbonic acids is increased from C9 to C11 and then is declined. • Carbon chain length determines the potency of PFAS with a V-shaped pattern. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid dehydrogenase/steroid Δ5,4-isomerase 1 (3β-HSD1) plays a critical role in the biosynthesis of progesterone from pregnenolone in the human placenta to maintain normal pregnancy. Whether they inhibit placental 3β-HSD1 and mode of inhibition remains unclear. In this study, we screened 21 pesticides and fungicides in five classes to inhibit human 3β-HSD1 and compared them to rat homolog 3β-HSD4. 3β-HSD activity was measured by catalyzing pregnenolone to progesterone in the presence of NAD+. Of the 21 chemicals, azoles (difenoconazole), thiocarbamates (thiram and ferbam) and organochlorine (hexachlorophene) significantly inhibited human 3β-HSD1 with half maximal inhibitory concentration (IC 50) values of 2.77, 0.24, 0.68, and 17.96 μM, respectively. We also found that difenoconazole, ferbam and hexachlorophene are mixed/competitive inhibitors of 3β-HSD1 while thiram is a mixed/noncompetitive inhibitor. Docking analysis showed that difenoconazole and hexachlorophene bound steroid-binding site. Difenoconazole and hexachlorophene except thiram and ferbam also significantly inhibited rat 3β-HSD4 activity with IC 50 of 1.12 and 2.28 µM, respectively. Thiram and ferbam significantly inhibited human 3β-HSD1 possibly by interfering with cysteine residues, while they had no effects on rat 3β-HSD4. In conclusion, some pesticides potently inhibit placental 3β-HSD, leading to the reduction of progesterone formation. [Display omitted] • Difenoconazole, thiram, and ferbam are potent human 3β-HSD1 inhibitors. • Hexachlorophene is a moderate human 3β-HSD1 inhibitor. • The species-dependent difference for inhibition of placental 3β-HSD. • Thiram and ferbam inhibit human 3β-HSD1 by targeting cysteine residues. • Thiram and ferbam do not inhibit rat 3β-HSD4. [ABSTRACT FROM AUTHOR]

Bisphenols, estrogenic endocrine-disrupting chemicals, disrupt at least one of three endocrine pathways (estrogen, androgen, and thyroid). 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) is a steroidogenic enzyme that catalyzes the activation of estradiol from estrone in human placenta and rat ovary. However, whether bisphenols inhibit 17β-HSD1 and the mode of action remains unclear. This study we screened 17 bisphenols for inhibiting human 17β-HSD1 in placental microsomes and rat 17β-HSD1 in ovarian microsomes and determined 3D-quantitative structure-activity relationship (3D-QSAR) and mode of action. We observed some bisphenols with substituents were found to significantly inhibit both human and rat 17β-HSD1 with the most potent inhibition on human enzyme by bisphenol H (IC 50 = 0.90 μM) when compared to bisphenol A (IC 50 = 113.38 μM). Rat enzyme was less sensitive to the inhibition of bisphenols than human enzyme with bisphenol H (IC 50 = 32.94 μM) for rat enzyme. We observed an inverse correlation between IC 50 and hydrophobicity (expressed as Log P). Docking analysis showed that they bound steroid-binding site of 17β-HSD1. The 3D-QSAR models demonstrated that hydrophobic region, hydrophobic aromatic, ring aromatic, and hydrogen bond acceptor are key factors for the inhibition of steroid synthesis activity of 17β-HSD1. [Display omitted] • BPA analogues have been widely used but disrupt at least one of three endocrine pathways. • Bisphenols inhibit both human and rat 17β-HSD1. Rat enzyme was less sensitive than human enzyme. • Docking analysis showed that they bound steroid-binding site of 17β-HSD1. • 3D-QSAR models demonstrated HBA, HY, RA, HYA are key factors. • An inverse correlation between IC 50 and hydrophobicity (expressed as Log P). [ABSTRACT FROM AUTHOR]

Placenta contains 3β-hydroxysteroid dehydrogenase/steroid Δ5,4-isomerase (HSD3B), which catalyzes pregnenolone to progesterone for maintaining pregnancy. Perfluoroalkyl carbonic acids (PFC) are subclass of perfluoroalkyl substances containing 4–14 carbons (C4-C14) in the carbon backbone and are potential endocrine disruptors. Whether PFC inhibit HSD3B and structure-activity relationship (SAR) remains unclear. Herein, we screened 11 PFC for inhibiting human type I HSD3B (HSD3B1) and rat type IV HSD3B (HSD3B4) activities and determined SAR and mode of inhibition. HSD3B was measured by converting pregnenolone to progesterone assisted by NAD+ in placental microsomes. Of the 11 PFC, C9-C14 significantly inhibited human HSD3B1 activity at 100 μM. Half-maximal inhibitory concentration (IC 50) values of C9-C14 compounds were 363.56 ± 12.14, 12.78 ± 0.69, 6.54 ± 0.65, 20.88 ± 0.41, 118.35 ± 0.16, and 149.26 ± 21.67 μM, respectively. We determined Ki values and mode of inhibition of three most potent PFC (C10-C12), and found that they were mixed inhibitors against pregnenolone, with Ki values of 5.57 ± 4.37, 2.04 ± 2.26, and 9.93 ± 7.71, respectively. Docking analysis showed that they bound steroid-binding site. Effects of PFC on rat placental HSD3B4 were performed. Of the 11 PFC, C10-C12 significantly inhibited rat HSD3B4 activity at 100 μM. IC 50 values of C10-C12 compounds were 45.85 ± 1.49, 36.08 ± 1.50, and 88.74 ± 1.99 µM, respectively. Ki values and inhibition modes of the three most potent PFC (C10-C12) were studied. It was found that they were mixed inhibitors against pregnenolone, with Ki values of 48.16 ± 20.44, 36.28 ± 53.07, and 91.79 ± 21.75 μM, respectively. Docking analysis showed that they bound steroid-binding site of rat HSD3B4. In conclusion, PFC showed significant SAR differences. The potency of inhibiting HSD3B activity increased from C9 to C11, and then declined. Human HSD3B1 was more sensitive to the inhibition of rat HSD3B4. [Display omitted] • Some perfluoroalkyl carbonic acids are inhibitors of human HSD3B1 and rat HSD3B4. • PFC inhibit human and rat HSD3B depending on the carbon chain length. • The potency of PFC is increased from C9 to C11 and then is declined. [ABSTRACT FROM AUTHOR]

Perfluorotetradecanoic acid (PFTeDA) is a type of perfluoroalkyl acid that has been linked to various health effects in animals and humans. The study aimed to investigate the potential impact of PFTeDA exposure on Leydig cell development in rats during puberty. Understanding the effects of PFTeDA on Leydig cells is crucial as these cells play a significant role in male reproductive function. Male Sprague-Dawley rats were gavaged with PFTeDA at doses of 0, 1, 5, and 10 mg/kg/day from postnatal day 35–56. The serum hormone levels were measured and testicular transcriptome changes were analyzed by RNA-seq and verified by qPCR, and the levels of steroidogenesis-related proteins and energy regulators were measured. PFTeDA significantly reduced serum testosterone levels while slightly increasing LH levels. RNA-seq and qPCR analysis showed that genes responsive to oxidative phosphorylation (Naufa1 and Ndufs6) and steroidogenesis (Ldlr, Star, Cyp11a1) were markedly downregulated at ≥ 5 mg/kg, while those related to ferroptosis (Alox15) and cell senescence (Map2k3 and RT1-CE3) were significantly upregulated. PFTeDA markedly reduced SIRT1 (silent information regulator 1) /PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) and AMPKA (AMP activated kinase A), LC3B and Beclin1 (biomarkers for autophagy) levels while increasing phosphorylated mTOR. In vitro treatment of PFTeDA at 5 μM significantly reduced androgen output of Leydig cells from 35-day-old male rats while ferrostatin 1 (10 μM) reversed PFTeDA-mediated inhibition. In conclusion, the inhibitory effects of PFTeDA on pubertal rat Leydig cell development are possibly regulated by inducing ferroptosis thereby downregulating SIRT1/AMPKA/ autophagy pathways, eventually resulting in reduced steroidogenesis. [Display omitted] • PFTeDA reduces serum testosterone levels in puberty. • PFTeDA decreases Leydig cell number after exposure in late puberty. • PFTeDA downregulates Leydig cell steroidogenesis-related gene expression. • PFTeDA induces ROS and cell senescence. • Ferrostatin-1 reverses PFTeDA-mediated inhibition on androgen output by Leydig cells. [ABSTRACT FROM AUTHOR]

Objective. To determine if supplemental intraarticular α2-macroglobulin (α2M) has a chondroprotective effect in a rat model of osteoarthritis (OA). Methods. Using Western blotting, mass spectrometry, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry, α2M was identified as a potential therapeutic agent through a comparison of α2M concentrations in serum, synovial fluid (SF), and cartilage from normal subjects and patients with OA. In cultured chondrocytes, the effects of α2M on interleukin-1 (IL-1)-induced cartilage catabolic enzymes were evaluated by Luminex assay and ELISA. In vivo effects on cartilage degeneration and matrix metalloproteinase 13 (MMP-13) concentration were evaluated in male rats (n =120) randomized to 1 of 4 treatments: 1) anterior cruciate ligament transection (ACLT) and saline injections, 2) ACLT and 1 IU/kg injections of α2M, 3) ACLT and 2 IU/kg injections of α2M, or 4) sham operation and saline injections. Rats were administered intraarticular injections for 6 weeks. The concentration of MMP-13 in SF lavage fluid was measured using ELISA. OA-related gene expression was quantified by real-time quantitative polymerase chain reaction. The extent of OA progression was graded by histologic examination. Results. In both normal subjects and OA patients, α2M levels were lower in SF as compared to serum, and in OA patients, MMP-13 levels were higher in SF than in serum. In vitro, α2M inhibited the induction of MMP-13 by IL-1 in a dose-dependent manner in human chondrocytes. In the rat model of ACLT OA, supplemental intraarticular injection of α2M reduced the concentration of MMP-13 in SF, had a favorable effect on OA-related gene expression, and attenuated OA progression. Conclusion. The plasma protease inhibitor α2M is not present in sufficient concentrations to inactivate the high concentrations of catabolic factors found in OA SF. Our findings suggest that supplemental intraarticular α2M provides chondral protection in posttraumatic OA. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11β-HSD1 were investigated. The potencies of inhibition on human 11β-HSD1 were bisphenol H (IC50, 0.75 µM) > bisphenol G (IC50, 5.06 µM) > diallyl bisphenol A (IC50, 13.36 µM) > dimethyl bisphenol A (IC50, 30.18 µM) > bisphenol A dimethyl ether (IC50, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11β-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11β-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11β-HSD isoforms. [ABSTRACT FROM AUTHOR]

Human 3β-hydroxysteroid dehydrogenase type I (HSD3B1) and rat type IV (HSD3B4) in placentas catalyze the conversion of pregnenolone to progesterone, which plays a key role in maintaining pregnancy. Many phenolic compounds potentially inhibit HSD3B in placentas as endocrine disruptors. In this study, the effects of 16 phenolic compounds on the activity of human HSD3B1 and rat HSD3B4 were determined and the structure-activity relationship was compared. HSD3B1 in human placental microsomes and HSD3B4 in rat placental microsomes were used to measure their activities and pregnenolone and NAD+ were used as substrates. Of the 16 phenolic compounds, 4-nonylphenol, pentabromophenol, and 2-bromophenol resulted in residual human HSD3B1 activity lower than 50 % and 4-nonylphenol and pentabromophenol resulted in residual rat HSD3B4 activity lower than 50 %. 4-Nonylphenol, pentabromophenol, and 2-bromophenol were mixed inhibitors of human HSD3B1, with Ki values of 2.31, 3.58 and 4.86 µM, respectively, while 4-nonylphenol and pentabromophenol were noncompetitive inhibitors of rat HSD3B4 with Ki values of 20.86 and 141.8 µM. Molecular docking showed that 4-nonylphenol, pentabromophenol, and 2-bromophenol docked to the active sites of human HSD3B1 and rat HSD3B4, and the shift of residue S125 in human HSD3B1 to T125 in rat HSD3B4 could explain the species-dependent difference in their inhibitory potency and mode of action. This study demonstrates that 4-nonylphenol, pentabromophenol, and 2-bromophenol are mixed inhibitors of human placental HSD3B1, while 4-nonylphenol and pentabromophenol are noncompetitive inhibitors of rat HSD3B4, possibly blocking the placental steroidogenesis. [Display omitted] • Some phenolic compounds are inhibitors of human HSD3B1 and rat HSD3B4. • 4-Nonylphenol, pentabromophenol, 2-bromophenol potently inhibit human HSD3B1. • 4-Nonylphenol and pentabromophenol moderately inhibit rat HSD3B4. • Straight long-chain alkyl substitution in 4-position is critical for the inhibition of HSD3B. • Shift of S125 in human HSD3B1 to T125 in rat HSD3B4 is possibly related to reduction of inhibitory potency of phenols in rats. [ABSTRACT FROM AUTHOR]

Benzophenone chemicals (BPs) have been developed to prevent the adverse effects of UV radiation and they are widely contaminated. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyze the conversion of inactive glucocorticoid to active glucocorticoid, playing critical role in many physiological function. However, the direct effect of BPs on human, pig, rat, and mouse 11β-HSD1 remains unclear. In this study, we screened the inhibitory strength of 12 BPs on 4 species, and performed the structure-activity relationship (SAR) and in silico docking analysis. The inhibitory potency of BPs was: for human 11β-HSD1, BP6 (IC 50 = 18.76 μM) > BP8 (40.84 μM) > BP (88.89 μM) > other BPs; for pig 11β-HSD1, BP8 (45.57 μM) > BP6 (59.44 μM) > BP2 (65.12 μM) > BP (135.56 μM) > other BPs; for rat 11β-HSD1, BP7 (67.17 μM) > BP (68.83 μM) > BP8 (133.04 μM) > other BPs; and for mouse 11β-HSD1, BP8 (41.41 μM) > BP (50.61 μM) > other BPs. These BP chemicals were mixed/competitive inhibitors of these 11β-HSD1 enzymes. The 2,2′-dihydroxy substitutions in two benzene rings play a key role in enhancing the effectiveness of inhibiting 11β-HSD1, possibly via increasing hydrogen bond interactions. Docking analysis shows that these BPs bind to NADPH/glucocorticoid binding sites and forms hydrogen bonds with catalytic residues Ser and/or Tyr. In conclusion, this study demonstrates that BP chemicals can inhibit 11β-HSD1 from 4 species, and there are subtle species-dependent difference in the inhibitory strength and structural variations of BPs. [Display omitted] • BP, BP6 and BP8 significantly inhibited human 11β-HSD1 activity • BP, BP2, BP6 and BP8 significantly inhibited pig 11β-HSD1 activity • BP, BP2, BP3, BP7and BP8 significantly inhibited rat 11β-HSD1 activity, with the residual activity of less than 50% for BP, BP7, and BP8 when compared with the control • BP and BP8 significantly inhibited mouse 11β-HSD1 activity • These BPs bind to NADPH/glucocorticoid binding sites and forms hydrogen bonds with catalytic residues Ser and/or Tyr [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the effect of 11 organochlorine pesticides on human and rat 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) in human placental and rat ovarian microsome and on estradiol production in BeWo cells. The results showed that the IC 50 values for endosulfan, fenhexamid, chlordecone, and rhothane on human 17β-HSD1 were 21.37, 73.25, 92.80, and 117.69 μM. Kinetic analysis revealed that endosulfan acts as a competitive inhibitor, fenhexamid as a mixed/competitive inhibitor, chlordecone and rhothane as a mixed/uncompetitive inhibitor. In BeWo cells, all insecticides except endosulfan significantly decreased estradiol production at 100 μM. For rats, the IC 50 values for dimethomorph, fenhexamid, and chlordecone were 11.98, 36.92, and 109.14 μM. Dimethomorph acts as a mixed inhibitor, while fenhexamid acts as a mixed/competitive inhibitor. Docking analysis revealed that endosulfan and fenhexamid bind to the steroid-binding site of human 17β-HSD1. On the other hand, chlordecone and rhothane binds to a different site other than the steroid and NADPH-binding site. Dimethomorph binds to the steroid/NADPH binding site, and fenhexamid binds to the steroid binding site of rat 17β-HSD1. Bivariate correlation analysis showed a positive correlation between IC 50 values and LogP for human 17β-HSD1, while a slight negative correlation was observed between IC 50 values and the number of HBA. ADMET analysis provided insights into the toxicokinetics and toxicity of organochlorine pesticides. In conclusion, this study identified the inhibitory effects of 3–4 organochlorine pesticides and binding mechanisms on human and rat 17β-HSD1, as well as their impact on hormone production. [Display omitted] • Endosulfan inhibits human 17β-HSD1. • Endosulfan binds to steroid-bind site of human 17β-HSD1. • Endosulfan is a competitive inhibitor of human 17β-HSD1. • Species-dependent inhibition of organochlorines on human and rat 17β-HSD1. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are widely used synthetic chemicals that persist in the environment and bioaccumulate in animals and humans. There is growing evidence that PFAS exposure adversely impacts neurodevelopment and neurological health. Steroid 5α-reductase 1 (SRD5A1) plays a key role in neurosteroidogenesis by catalyzing the conversion of testosterone or pregnenolone to neuroactive steroids, which influence neural development, cognition, mood, and behavior. This study investigated the inhibitory strength and binding interactions of 18 PFAS on human and rat SRD5A1 activity using enzyme assays, molecular docking, and structure-activity relationship analysis. Results revealed that C9–C14 PFAS carboxylic acid at 100 μM significantly inhibited human SRD5A1, with IC 50 values ranged from 10.99 μM (C11) to 105.01 μM (C14), and only one PFAS sulfonic acid (C8S) significantly inhibited human SRD5A1 activity, with IC 50 value of 8.15 μM. For rat SRD5A1, C9–C14 PFAS inhibited rat SRD5A1, showing the similar trend, depending on carbon number of the carbon chain. PFAS inhibit human and rat SRD5A1 in a carbon chain length-dependent manner, with optimal inhibition around C11. Kinetic studies indicated PFAS acted through mixed inhibition. Molecular docking revealed PFAS bind to the domain between NADPH and testosterone binding site of both SRD5A1 enzymes. Inhibitory potency correlated with physicochemical properties like carbon number of the carbon chain. These findings suggest PFAS may disrupt neurosteroid synthesis and provide insight into structure-based inhibition of SRD5A1. [Display omitted] • Some per- and polyfluoroalkyl substances potently inhibit human SRD5A1. • Some per- and polyfluoroalkyl substances inhibit rat SRD5A1. • Perfluoroalkyl carboxylic acids inhibit human and rat SRD5A1 depending on carbon chain length. • Per- and polyfluoroalkyl substances act mixed inhibition of human and rat SRD5A1. [ABSTRACT FROM AUTHOR]

Curcuminoids have many pharmacological effects. They or their metabolites may have side effects by suppressing 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3). Herein, we investigated the inhibition of curcuminoids and their metabolites on human and rat 17β-HSD3 and analyzed their structure-activity relationship (SAR) and performed in silico docking. Curcuminoids and their metabolites ranked in terms of IC 50 values against human 17β-HSD3 were bisdemethoxycurcumin (0.61 μM) > curcumin (8.63 μM) > demethoxycurcumin (9.59 μM) > tetrahydrocurcumin (22.04 μM) > cyclocurcumin (29.14 μM), and those against rat 17β-HSD3 were bisdemethoxycurcumin (3.94 μM) > demethoxycurcumin (4.98 μM) > curcumin (9.62 μM) > tetrahydrocurcumin (45.82 μM) > cyclocurcumin (143.5 μM). The aforementioned chemicals were mixed inhibitors for both enzymes. Molecular docking analysis revealed that they bind to the domain between the androstenedione and NADPH active sites of 17β-HSD3. Bivariate correlation analysis showed a positive correlation between LogP and pKa of curcumin derivatives with their IC 50 values. Additionally, a 3D-QSAR analysis revealed that a pharmacophore model consisting of three hydrogen bond acceptor regions and one hydrogen bond donor region provided a better fit for bisdemethoxycurcumin compared to curcumin. In conclusion, curcuminoids and their metabolites possess the ability to inhibit androgen biosynthesis by directly targeting human and rat 17β-HSD3. The inhibitory strength of these compounds is influenced by their lipophilicity and ionization characteristics. [Display omitted] • Bisdemethoxycurcumin potently inhibits human 17β-HSD3. • Curcumin derivatives inhibit human 17β-HSD3 with structure differences. • Curcuminoids potently inhibit testosterone secretion in LNCaP cells. • Curcumin derivatives inhibit rat 17β-HSD3 with structure differences. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a widely used plastic material and its potential endocrine disrupting effect has restricted its use and increasing use of BPA alternatives has raised health concerns. However, the effect of bisphenol alternatives on steroidogenesis remains unclear. The objective of this study was to compare inhibitory potencies of 10 BPA alternatives in the inhibition of gonadal 3β-hydroxysteroid dehydrogenase (3β-HSD) in three species (human, rat and mouse). The inhibitory potency for human 3β-HSD2, rat 3β-HSD1, and mouse 3β-HSD6 ranged from bisphenol FL (IC 50 , 3.32 μM for human, 5.19 μM for rat, and 3.26 μM for mouse) to bisphenol E, F, and thiodiphenol (ineffective at 100 μM). Most BPA alternatives were mixed inhibitors of gonadal 3β-HSD and they dose-dependently inhibited progesterone formation in KGN cells. Molecular docking analysis showed that all BPA analogs bind to steroid and NAD+ active sites. Lipophilicity of BPA alternatives was inversely correlated with IC 50 values. In conclusion, BPA alternatives mostly can inhibit gonadal 3β-HSDs and lipophilicity determines their inhibitory strength. [Display omitted] • BPA analogs inhibit human, rat, and mouse gonadal 3β-HSD more potently than BPA. • BPFL is the most potent inhibitor of human, rat, and mouse 3β-HSD. • Lipophilicity (LogP) determines the inhibitory strength on human, rat and mouse gonadal 3β-HSD. • Most BPA analogs are mixed inhibitors of 3β-HSD. [ABSTRACT FROM AUTHOR]

The use of alternative substances to replace bisphenol A (BPA) has been encouraged. The objective of this study was to evaluate the effects of BPA and 9 BPA alternatives on human and rat aromatase (CYP19A1) in human and rat placental microsomes. The results revealed that bisphenol A, AP, B, C, E, F, FL, S, and Z, and 4,4′-thiodiphenol (TDP) inhibited human CYP19A1 and bisphenol A, AP, B, C, FL, Z, and TDP inhibited rat CYP19A1. The IC 50 values of human CYP19A1 ranged from 3.3 to 172.63 μM and those of rat CYP19A1 ranged from 2.20 to over 100 μM. BPA alternatives were mixed/competitive inhibitors and inhibited estradiol production in BeWo placental cells. Molecular docking analysis showed that BPA alternatives bind to the domain between heme and steroid and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were one hydrogen bond donor, one hydrophobic region, and one ring aromatic hydrophobic region. Bivariate correlation analysis showed that molecular weight, alkyl atom weight, and LogP of BPA alternatives were inversely correlated with their IC 50 values. In conclusion, BPA alternatives can inhibit human and rat CYP19A1 and the lipophilicity and the substituted alkyl size determines their inhibitory strength. [Display omitted] • Bisphenol A (BPA) alternatives inhibit human placental CYP19A1. • Some BPA alternatives suppress estradiol production by human BeWo cells. • Hydrophobicity determines the inhibitory strength of BPA alternatives on CYP19A1. • BPA alternatives bind to steroid-binding site and domain between steroid and heme of CYP19A1. [ABSTRACT FROM AUTHOR]

In traditional Chinese medicine, licorice (the roots of Glycyrrhiza glabra and G. inflata) has been used to treat inflammation and sexual debility for over 1000 years. Pharmacological studies have identified many biologically active chalcone derivatives from licorice. Human 3β-Hydroxysteroid dehydrogenase 2 (h3β-HSD2) catalyzes the formation of precursors for sex hormones and corticosteroids, which play critical roles in reproduction and metabolism. We explored inhibition and mode action of chalcones of inhibiting h3β-HSD2 and compared it with rat 3β-HSD1. We investigated the inhibition of 5 chalcones on h3β-HSD2 and compared species-dependent difference with 3β-HSD1. The inhibitory strength on h3β-HSD2 was isoliquiritigenin (IC 50 , 0.391 μM) > licochalcone A (0.494 μM) > licochalcone B (1.485 μM) > echinatin (1.746 μM) >chalcone (100.3 μM). The inhibitory strength on r3β-HSD1 was isoliquiritigenin (IC 50 , 0.829 μM) > licochalcone A (1.165 μM) > licochalcone B (1.866 μM) > echinatin (2.593 μM) > chalcone (101.2 μM). Docking showed that all chemicals bind steroid and/or NAD+-binding site with the mixed mode. Structure-activity relationship analysis showed that strength was correlated with chemical's hydrogen bond acceptor. Some chalcones are potent h3β-HSD2 and r3β-HSD1 inhibitors, possibly being potential drugs to treat Cushing's syndrome or polycystic ovarian syndrome. [Display omitted] • Chalcone analogues inhibit human 3β-HSD2 activity. • Chalcone analogues inhibit rat testicular 3β-HSD1 activity. • Isoliquiritigenin is the most potent inhibitor to inhibit both enzymes. • Hydrogen acceptor and donor number of chalcones determines the inhibitory potency. • There are clear structure-activity relationships for chalcone analogues. [ABSTRACT FROM AUTHOR]

Some halogenated bisphenol A (BPA) derivatives (tetrabromobisphenol A, TBBPA, and tetrachlorobisphenol A, TCBPA) are produced in a high volume and exist in PM 2.5 after waste burning. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) is a critical enzyme for placental function. However, whether halogenated bisphenols inhibit 11β-HSD2 and the mode of action remains unclear. The objective of this study was to investigate BPA derivatives on human and rat placental 11β-HSD2. The inhibitory strength on human 11β-HSD2 was TBBPA (IC 50 , 0.665 μM)>TCBPA (2.22 μM)>trichloro BPA (TrCBPA, 19.87 μM)>tetrabromobisphenol S (TBBPS, 36.76 μM)>monochloro BPA (MCBPA, 104.0 μM)>BPA (144.9 μM)>bisphenol S. All chemicals are mixed and competitive inhibitors. Rat 11β-HSD2 was less sensitive to BPA derivatives, with TBBPA (IC 50 , 96.63 μM)>TCBPA (99.69 μM)>TrCBPA (104.1 μM)>BPA (117.1 μM)>others. Docking analysis showed that BPA derivatives bind steroid active sites. Structure-activity relationship revealed that halogen atoms and LogP were inversely correlated with inhibitory strength on human 11β-HSD2, while LogS and polar desolvation energy were positively correlated with the inhibitory strength. In conclusion, halogenated BPA derivatives are mostly potent inhibitors on human 11β-HSD2 and there is structure-dependent inhibition. [Display omitted] • Halogenated BPA derivatives potently inhibit human and rat 11β-HSD2. • TBBPA is the most potent inhibitor of human 11β-HSD2. • Rat 11β-HSD2 is less sensitive than human enzyme to halogenated BPA derivatives. • Halogen atoms, solubility, hydrophobicity determines the inhibitory potency. Halogenated bisphenol A derivatives inhibit human 11β-HSD2 activity, thereby leading to placental dysfunction and fetal growth retardation. [ABSTRACT FROM AUTHOR]

In traditional Chinese medicine, curcuma longa L has been applied to treat pain and tumour-related symptoms for over thousands of years. Curcuminoids, polyphenolic compounds, are the main pharmacological component from the rhizome of Curcuma longa L. Pharmacological investigations have found that curcuminoids have many pharmacological activities of anti-inflammatory, anti-tumour, and anti-metastasis. 3β-Hydroxysteroid dehydrogenase (3β-HSD1) catalyses the production of steroid precursors for androgens and estrogens, which play an essential role in cancer metastasis. We explored the potency and mode of action of curcuminoids and their metabolites of inhibiting 3β-HSD1 activity and compared the species difference between human and rat. In this study, we investigated the direct inhibition of 6 curcuminoids on human placental 3β-HSD1 activity and compared the species-dependent difference in human 3β-HSD1 and rat placental homolog 3β-HSD4. Results : The inhibitory potency of curcuminoids on human 3β-HSD1 was demethoxycurcumin (IC 50 , 0.18 μM) > bisdemethoxycurcumin (0.21 μM)>curcumin (2.41 μM)> dihydrocurcumin (4.13 μM)>tetrahydrocurcumin (15.78 μM)>octahydrocurcumin (ineffective at 100 μM). The inhibitory potency of curcuminoids on rat 3β-HSD4 was bisdemethoxycurcumin (3.34 μM)>dihydrocurcumin (5.12 μM)>tetrahydrocurcumin (41.82 μM)>demethoxycurcumin (88.10 μM)>curcumin (137.06 μM)> octahydrocurcumin (ineffective at 100 μM). Human choriocarcinoma JAr cells with curcuminoid treatment showed that these chemicals had similar potency to inhibit progesterone secretion under basal and 8bromo-cAMP stimulated conditions. Docking analysis showed that all chemicals bind pregnenolone-binding site with mixed/competitive mode for 3β-HSD. Some curcuminoids are potent human placental 3β-HSD1 inhibitors, possibly being potential drugs to treat prostate cancer and breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Many insecticides and fungicides are endocrine-disrupting compounds, which possibly interfere with the placental endocrine system. In the placenta, 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerase type 1 (HSD3B1) is the major steroidogenic enzyme, which makes progesterone from pregnenolone to support the placental stability. In this study, we screened 12 classes of insecticides and fungicides to inhibit placental HSD3B1 activity and compared them to the rat homolog type 4 (HSD3B4) isoform. Human HSD3B1 activity and rat HSD3B4 activity were measured in the presence of 200 nM pregnenolone and 0.2 mM NAD+ and 100 μM of test chemical. Triclosan, triflumizole, dichlone, and oxine at 100 μM significantly inhibited human HSD3B1 activity with the residual activity being less than 50% of the control. Further study showed that the half-maximal inhibitory concentration (IC 50) values of triclosan, triflumizole, dichlone, and oxine were 85.53 ± 9.14, 73.75 ± 3.42, 2.54 ± 0.40, and 102.93 ± 6.10 μM, respectively. In the presence of pregnenolone, triclosan, triflumizole, and dichlone were mixed inhibitors of HSD3B1, while oxine was a noncompetitive inhibitor. In the presence of NAD+, triclosan exhibited competitive inhibition while triflumizole possessed uncompetitive inhibition. Docking analysis showed that triclosan bound NAD+-binding site, while triflumizole, dichlone, and oxine mostly bound steroid-binding site. When the effect of these insecticides on rat placental HSD3B4 activity was screened in the presence of 200 nM pregnenolone, atrazine, triclosan, triflumizole, oxine, cyprodinil, and diphenyltin at 100 μM significantly inhibited rat HSD3B4 activity, with IC 50 values of triclosan, triflumizole, oxine, and cyprodinil were 82.99 ± 6.48, 35.45 ± 2.73, 105.59 ± 12.04, and 43.37 ± 3.00 μM, respectively. The mode action analysis showed that t riflumizole and cyprodinil were almost competitive inhibitors, while triclosan and oxine were almost noncompetitive inhibitors of rat HSD3B4. Docking analysis showed that triclosan and oxine bound cofactor NAD+ binding residues more than steroid-binding residues of rat HSD3B4 while triflumizole and cyprodinil bound most pregnenolone-interactive residues. In conclusion, some insecticides such as triclosan, triflumizole, and oxine can effectively inhibit both human and rat placental HSD3B activity and they have unique mode action due to the structure difference. [Display omitted] • Triclosan, triflumizole, and dichlone are mixed inhibitors of human HSD3B1. • Triclosan, triflumizole, cyprodinil are mixed inhibitors of rat HSD3B4. • Oxine is a non-competitive inhibitor of human HSD3B1 and rat HSD3B4. • Primary structure difference in catalytic residue S125T may explain the species-dependent difference of these chemicals. [ABSTRACT FROM AUTHOR]