Flavio Martínez

Fluoride-induced disruption of reproductive hormones in men

Fluoride-induced reproductive effects have been reported in experimental models and in humans. However, these effects were found in heavily exposed scenarios. Therefore, in this work our objective was to study reproductive parameters in a population exposed to fluoride at doses of 3-27 mg/day (high-fluoride-exposed group-HFEG). Urinary fluoride levels, semen parameters, and reproductive hormones in serum (LH, FSH, estradiol, prolactin, inhibin-B, free and total testosterone) were measured. Results were compared with a group of individuals exposed to fluoride at lower doses: 2-13 mg/day (low-fluoride-exposed group-LFEG). A significant increase in FSH (P<0.05) and a reduction of inhibin-B, free testosterone, and prolactin in serum (P<0.05) were noticed in the HFEG. When HFEG was compared to LFEG, a decreased sensitivity was found in the FSH response to inhibin-B (P<0.05). A significant negative partial correlation was observed between urinary fluoride and serum levels of inhibin-B (r=-0.333, P=0.028) in LFEG. Furthermore, a significant partial correlation was observed between a chronic exposure index for fluoride and the serum concentrations of inhibin-B (r=-0.163, P=0.037) in HFEG. No abnormalities were found in the semen parameters studied in the present work, neither in the HFEG, nor in the LFEG. The results obtained indicate that a fluoride exposure of 3-27 mg/day induces a subclinical reproductive effect that can be explained by a fluoride-induced toxic effect in both Sertoli cells and gonadotrophs.

Environmental Health Assessment of Deltamethrin in a Malarious Area of Mexico: Environmental Persistence, Toxicokinetics, and Genotoxicity in Exposed Children

We reported previously that children are exposed to deltamethrin in malarious areas. In the present work we explored the levels of this insecticide in soil samples and also obtained relevant toxico-kinetic data of deltamethrin in exposed children. Results show that, after spraying, indoor levels of deltamethrin in soil samples were higher than outdoor levels. The mean half-life estimated with these data was 15.5 days for outdoor samples and 15.4 days for indoor samples. Children’s exposure to deltamethrin was assessed using as biomarkers the urinary concentrations of the metabolites 3-phenoxybenzoic acid (3-PBA) and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br2CA). The mean level of both biomarkers reached a peak within the first 24 hr postexposure; 6 months after the initial exposure, urinary levels of 3-PBA and Br2CA were found at levels observed before exposure. Approximately 91% of the total 3-PBA or Br2CA was excreted during the first 3 days after exposure. Therefore, we estimated a half-life for this period, the values for 3-PBA and Br2CA being almost identical (13.5 vs. 14.5 hr). Finally, considering reports about the genotoxicity of deltamethrin, we assessed DNA damage in children before and 24 hr after indoor spraying of deltamethrin; we found no differences in the comet assay end points. In conclusion, we observed exposure to deltamethrin in children, but we did not find any relationship between soil concentrations of deltamethrin and urinary levels of the metabolites. At least for genotoxicity, the exposed children appeared not to be at risk.

Interaction of intrarenal adenosine and angiotensin II in kidney vascular resistance.

Purpose of the reviewThe adenosine–angiotensin II (ADO-AngII) interaction plays an important role in the regulation of glomerular filtration rate, vascular resistance and tubuloglomerular feedback. Although the interaction was described more than 30 years ago, the intrinsic mechanisms of the synergism between both autacoids remains incompletely understood. Recent findingsCurrent evidence suggests that ADO-metabolizing enzymes such as ecto-5′-nucleotidase or ADO deaminase, as well as enzymes that degrade ATP to adenosine, play an important role in the vasoconstrictor signals sent from the macula densa to the afferent arterioles when tubuloglomerular feedback is activated; increased ADO concentration induced by temporal infusion of AngII results in downregulation of A2 ADO receptors, leading to a predominant effect of A1 receptors; the alteration in the ADO receptors balance further contributes to the synergic interaction between ADO and AngII. SummaryThe ADO-metabolizing enzymes have become important regulators of the effects of ADO on the tone of the afferent and efferent arterioles. As AngII is able to increase de-novo renal ADO content through decrease of ADO-metabolizing enzymes, accumulation of ADO induces downregulation of ADO A2 receptor population without modifying ADO A1 receptor, thereby enhancing the constrictive effects of AngII in the renal vasculature.

Sodium-dependent adenosine transport is diminished in brush border membrane vesicles from hypothyroid rat kidney.

Abstract Studies of the uptake of [3H]adenosine ([3H]ADO) were performed using brush border membrane vesicles (BBMV) from normal (N) and hypothyroid (Tx) rat kidneys, to test if decreased Na+ reabsorption in hypothyroidism might be associated with abnormalities in ADO transport. [3H]ADO uptake (1–10 μmol) for both conditions was measured in the presence of Na+ (10–150 mmol/l); the effects of dipyridamole (10 μmol/l) and 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX, 10 μmol/l) were also studied. Na+-stimulated ADO uptake was decreased in Tx BBMV. Michaelis–Menten constants showed a decreased ADO carrier affinity (Km 2.46 ± 0.14 in N, vs Km 4.46 ± 0.88 μmol/l in Tx, P<0.05), with no change in the number of carriers (Vmax 295 ± 25 in N, vs 229.2 ± 56 pmol·min–1·mg protein in Tx). Na+ affinity remained unchanged (K Na+ 11.5 ± 3.5 in N, vs K Na+ 12.72 ± 0.7 mmol/l in Tx). Inhibition of Na+-dependent ADO transport was 50% in N as opposed to 58% in Tx with dipyridamole, and 72% in N versus 47% in Tx with PACPX. These results suggest that decreased Na+-dependent ADO cotransport contributes to the diminished tubular reabsorption that occurs in hypothyroidism.

Experimental hypothyroidism modifies specific binding of A1 and A2A analogues to adenosine receptors in the rat kidney

Binding kinetic studies with the adenosine analogues [3H]CPA (0.250–50 nM) and [3H]CGS21680 (0.1–100 nM) were performed in renal tissue from control (NL) and thyroidectomised (HTX) rats. We propose that the low renal adenosine content reported in hypothyroid rats may induce changes in the density and/or affinity of adenosine receptor, distributed in the cortex (C), outer medulla (OM), and inner medulla (IM) of the kidney. [3H]CPA and [3H]CGS21680 binding saturation isotherms were fitted by nonlinear regression analysis and evaluated by Furchgotts method. These results revealed high (KH) and low (KL) affinity (KD) sites for both compounds. As expected, a heterogeneous pattern was observed for Bmax and KD values. Bound [3H]CPA and [3H]CGS21680 were displaced by increasing concentrations of nonlabelled DPCPX and NECA, respectively, indicating the presence of A1 and A2A adenosine receptors distributed in the renal segments studied. The relative intrinsic efficacy (ɛ) for [3H]CPA and [3H]CGS21680 showed extreme values (far from 1.0), 0.5 in IM NL and 2.70 in IM HTX for [3H]CGS21680. Our results indicate that A2A adenosine receptor is predominant in IM from HTX, but A1 receptors are expressed preferentially in C in NL. We conclude that the changes observed in number, affinity, and ɛ for the A2A receptor in IM from HTX might be responsible from alterations in medullary function, that is, incapacity for urine concentration as observed in the hypothyroid kidney.

Urate and antioxidants inhibit Na + -adenosine transport in rat renal brush border membranes

The effects of urate and antioxidants were evaluated on sodium-dependent [3H]adenosine transport (Na+/ADO) in rat renal brush border membrane vesicles (BBMV). Na+/ADO was estimated for a range of adenosine concentrations of 1–10 μmol/l in BBMV preincubated with urate (0.5–50 μmol/l). Michaelis-Menten kinetics showed a significant increase in Km values from 2.48±0.49 μmol/l in control to 20.58±4.56 μmol/l with 50 μmol/l urate; Vmax (243±15 pmol/mg protein×min) was not modified. Menadione (10 μmol/l) significantly increased the Na+/ADO activity, from 17.57±5.50 in the control, to 27.70±7.60 pmol/mg prot.×min (a 1.60 times increase, p<0.05). This stimulation was prevented when BBMV were preincubated with either 1 μmol/l α-tocopherol (trolox) or urate. Similarly conjugated dienes and malonaldehyde were stimulated in a dose-dependent fashion by menadione and the effect was inhibited with 10 μmol/l trolox. The antioxidants probucol, captopril and allopurinol inhibited in a concentration-dependent manner the Na+/ADO (IC50 were 79±8, 100±9 and 89±9 nM, respectively). This effect might be specific on Km of the Na+/ADO, since 1 μmol/l trolox (IC50=1000±20 nM), inhibited Vmax but not Km of the Na+/glucose transport. Our results suggest that the Na+/ADO in BBMV is modified by agents that affect the redox status of the membranes.

Indomethacin and piroxicam inhibit Na+-adenosine transport in rat renal brush-border membranes.

The effects of the cyclooxygenase inhibitors, indomethacin and piroxicam, were evaluated on Na+-dependent [3H]adenosine transport in rat renal brush-border membranes of the outer renal cortex of the rat. Adenosine co-transport (1-10 microM) was estimated in the presence of 0.001-10 microM indomethacin and piroxicam. Both drugs inhibited the Na+-dependent transport in a dose-dependent manner with IC50 of 3.5 microM and 0.1 microM, respectively. The Na+-independent transport was not modified. Preincubations carried out on the vesicles with 10-50 microM arachidonic acid increased transport in a dose-dependent manner up to 1.7 times. Whereas 50 pM to 5 microM prostaglandin E2 in the presence of indomethacin did not change carrier activity, 5 microM prostaglandin E2 increased the Na+-dependent transport 1.5 times. Other prostanoid synthesis pathways were investigated with 10 microM nordihydroguaiaretic acid (lipoxygenase inhibitor), and 17-octadecynoic acid and clotrimazole (leukotriene and cytochrome P450 inhibitors). Our results demonstrated that the Na+-dependent adenosine transport in brush-border membranes was inhibited by indomethacin and piroxicam, suggesting that cyclooxygenase activity might modulate this co-transport.