Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets

To clarify species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) we measured the activity of four DEHP-metabolizing enzymes (lipase, UDP-glucuronyltransferase (UGT), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH)) in several organs (the liver, lungs, kidneys, and small intestine) of mice (CD-1), rats (Sprague–Dawley), and marmosets (Callithrix jacchus). Lipase activity, measured by the rate of formation of mono(2-ethylhexyl) phthalate (MEHP) from DEHP, differed by 27- to 357-fold among species; the activity was highest in the small intestines of mice and lowest in the lungs of marmosets. This might be because of the significant differences between Vmax/Km values of lipase for DEHP among the species. UGT activity for MEHP in the liver microsomes was highest in mice, followed by rats and marmosets. These differences, however, were only marginal compared with those for lipase activity. ADH and ALDH activity also differed among species; the activity of the former in the livers of marmosets was 1.6–3.9 times greater than in those of rats or mice; the activity of the latter was higher in rats and marmosets (2–14 times) than in mice. These results were quite different from those for lipase or UGT activity. Because MEHP is considered to be the more potent ligand to peroxisome proliferator-activated receptor involved in different toxic processes, a possibly major difference in MEHP-formation capacity could be also considered on extrapolation from rodents to humans.     

Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers

Objectives

This study was conducted to assess inter-species and inter-individual differences in the metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans and mice.

Methods

The activities of four DEHP-metabolizing enzymes [lipase, UDP-glucuronocyltransferase (UGT), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH)] were measured in the livers of 38 human subjects of various ages and in eight 129/Sv male mice.

Results

Microsomal lipase activity was significantly lower in humans than in mice. The V _max/K _m value in humans was one-seventh of that in mice, microsomal UGT activity in humans was a sixth of that in mice, and cytosolic ALDH activity for 2-ethylhexanal in humans was one-half of that in mice. In contrast, ADH activity for 2-ethylhexanol was twofold higher in humans than in mice. The total amount of DEHP urinary metabolites and the concentration of mono(2-ethylhexyl)phthalate (MEHP) were much higher in intact mice than in the U.S. general population based on data reported elsewhere, regardless of the similar estimated DEHP intake between these mice and the human reference population. However, mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) levels were higher in the latter than in the former. Of note, inter-subject variability in the activities of all enzymes measured was 10–26-fold.

Conclusion

The inter-individual variation in the metabolism of DEHP in humans may be greater than the difference between mice and humans (inter-species variation), and both may affects the risk assessment of DEHP.     

The Association of Prenatal Exposure to Perfluorinated Chemicals with Maternal Essential and Long-Chain Polyunsaturated Fatty Acids during Pregnancy and the Birth Weight of Their Offspring: The Hokkaido Study

Background

Fatty acids (FAs) are essential for fetal growth. Exposure to perfluorinated chemicals (PFCs) may disrupt FA homeostasis, but there are no epidemiological data regarding associations of PFCs and FA concentrations.

Objectives

We estimated associations between perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) concentrations and maternal levels of FAs and triglyceride (TG) and birth size of the offspring.

Methods

We analyzed 306 mother–child pairs in this birth cohort between 2002 and 2005 in Japan. The prenatal PFOS and PFOA levels were measured in maternal serum samples by liquid chromatography–tandem mass spectrometry. Maternal blood levels of nine FAs and TG were measured by gas chromatography–mass spectrometry and TG E-Test Wako kits, respectively. Information on infants’ birth size was obtained from participant medical records.

Results

The median PFOS and PFOA levels were 5.6 and 1.4 ng/mL, respectively. In the fully adjusted model, including maternal age, parity, annual household income, blood sampling period, alcohol consumption, and smoking during pregnancy, PFOS but not PFOA had a negative association with the levels of palmitic, palmitoleic, oleic, linoleic, α-linolenic, and arachidonic acids (p < 0.005) and TG (p-value = 0.016). Female infants weighed 186.6 g less with mothers whose PFOS levels were in the fourth quartile compared with the first quartile (95% CI: –363.4, –9.8). We observed no significant association between maternal levels of PFOS and birth weight of male infants.

Conclusions

Our data suggest an inverse association between PFOS exposure and polyunsaturated FA levels in pregnant women. We also found a negative association between maternal PFOS levels and female birth weight.

Citation

Kishi R, Nakajima T, Goudarzi H, Kobayashi S, Sasaki S, Okada E, Miyashita C, Itoh S, Araki A, Ikeno T, Iwasaki Y, Nakazawa H. 2015. The association of prenatal exposure to perfluorinated chemicals with maternal essential and long-chain polyunsaturated fatty acids during pregnancy and the birth weight of their offspring: the Hokkaido Study. Environ Health Perspect 123:1038–1045; http://dx.doi.org/10.1289/ehp.1408834     

Levels of volatile organic compounds in homes in Dalian,China

This paper measured selected individual volatile organic compounds (VOCs), including formaldehyde, in residences in Dalian, evaluated the association between the apartment characteristics and VOC concentrations, and explored the associations between chemicals and sick building syndrome (SBS). Higher VOC concentrations were measured indoors than outdoors in summer (August to September) and winter (January to March) in Dalian, and there were no strong correlations between the indoor and outdoor concentrations of most VOCs. This indicates the dominance of indoor sources as compared to outdoor sources. Formaldehyde was the most abundant compound in this study, followed by toluene, benzene, xylene, and styrene. These pollutants increase the occurrence of SBS. Thus, the VOC levels in dwellings in Dalian should be regulated, in view of SBS risks.     

Hearing loss in patients with enlarged vestibular aqueduct: Air-bone gap and audiological Bing test

The Bing test is based on the principle that occlusion of the external auditory meatus improves the perception of bone-conducted sounds unless there is a conductive hearing impairment. An air-bone gap has been reported in patients with large vestibular aqueduct (LVA) syndrome without apparent middle ear dysfunction. We therefore performed the Bing test on nine patients with this syndrome to evaluate whether it is associated with an air-bone gap or middle ear dysfunction. Bone conduction thresholds did not change significantly during the Bing test in any patient. Because an air-bone gap is observed in patients with abnormal communication between the inner ear and cerebrospinal fluid through the LVA, dehiscent superior canal, or dilated inner ear meatus; we propose that a ‘three windows’ model (in which the abnormal communication provided by the enlarged endolymphatic duct and sac in LVA acts as the ‘third window’ for sound conductance) might explain the air-bone gap in such patients.     

Anesthetic management of a patient with a history of Batista procedure for dilated cardiomyopathy undergoing gastric surgery

We experienced anesthetic management for an operation to remove a hemorrhagic gastric submucosal tumor in a patient who had undergone left ventricular volume reduction (the Batista procedure) for dilated cardiomyopathy (DCM) 2 years previously. Preoperative evaluations indicated the relapse of severe DCM. Intravenous and epidural anesthesia was employed with the aid of an intraaortic balloon pump (IABP). Safe anesthetic management was achieved under the guidance of a Swan-Ganz catheter without inducing overreduction of afterload or excessive preload.     

Effects of pregnancy, age and sex in the metabolism of styrene in rat liver in relation to the regulation of cytochrome P450 enzymes

To elucidate the effect of maternal styrene exposure, which is due to various postnatal changes in the development and behavior of offspring, we investigated pregnancy-induced changes in the metabolism of styrene in rat liver in relation to the regulation of cytochrome P450 enzymes. We also examined age and sex-induced changes in the metabolism of styrene. Pregnancy appeared to exert a negative effect on cytochrome P450 content at the late stage, whereas microsomal protein content showed little change during pregnancy. Pregnancy significantly decreased the rate of formation of styrene glycol at the late stage. The percentage of remaining activity in microsomes exposed to anti-CYP2E1 was lower than that exposed to anti-CYP2C11/6 in pregnant and non-pregnant female rats and immature male rats, indicating that CYP2E1 contributes to the metabolism of styrene more than CYP2C11/6 in these rats. Although pregnancy seemed to decrease styrene metabolism, the contribution of CYP2E1 seemed to be slightly increasing. In conclusion, pregnancy clearly influences the metabolism of styrene as well as other characteristic factors such as age and sex. It is very important to elucidate the changes in specific P450 isozyme composition related to their characteristic modification and in their affinity for chemicals.     

Linking numeracy and asthma-related quality of life

Objective

To examine the correlation of numerical skills used in patients’ self-management of asthma with asthma-related quality of life (AQOL).

Methods

Adults with moderate–severe asthma completed the Asthma Numeracy Questionnaire (ANQ), assessments of reading comprehension and self-efficacy, and the mini-Asthma Quality of Life Questionnaire (miniAQLQ). The numeracy-AQOL relationship was evaluated in the context of potential confounders (demographic variables) and mediators (e.g. income and self-efficacy), using tests of correlation then multivariable models to assess for confounders and mediators.

Results

80 adults with moderate or severe asthma were evaluated. Mean ANQ score was 2.3 ± 1.2 (range 0–4). ANQ was correlated with miniAQLQ (ρ = 0.24, p = 0.03). This association was sustained (ρ = 0.27, p = 0.02) when controlling for potential confounders significantly associated with AQOL (age, Latino ethnicity). The ANQ-miniAQLQ association was mediated by household income; the correlation was reduced by 81% when adjusting for income (ρ = 0.05, p = 0.65). In contrast, self-efficacy less strongly mediated this association; the correlation was reduced by 26% when controlled for self-efficacy (ρ = 0.20, p = 0.08).

Conclusion

Numerical skills needed for asthma self-management influence AQOL primarily through their impact on income and, to a lesser extent, on self-efficacy.

Practice implications

Adults with asthma will benefit from self-management instructions employing the simplest mathematical constructs whose understanding is confirmed by clinicians.     

Evidence for diazinon-mediated inhibition of cis-permethrin metabolism and its effects on reproductive toxicity in adult male mice

The potential toxicity resulting from combinatorial effects of organophosphorus and pyrethroid insecticides are not completely known. We evaluated male reproductive toxicity in mice co-exposed to diazinon and cis-permethrin. Nine-week-old male Sv/129 mice were exposed to diazinon (10μmol/kg/day) or cis-permethrin (90μmol/kg/day) alone or in combination (100μmol/kg/day), or vehicle (corn oil), for 6 weeks. Diazinon and the diazinon-permethrin mixture inhibited plasma and liver carboxylesterase activities. In the mixture group, urinary excretion of cis-permethrin metabolite 3-phenoxybenzoic acid decreased along with increased plasma and testicular concentrations of cis-permethrin, while excretion of diazinon metabolites, diethylphosphate and diethylthiophosphate, did not change, versus mice exposed to each chemical alone, which suggested that inhibition of carboxylesterase decreased the metabolic capacity to cis-permethrin. Though the co-exposure decreased testosterone biosynthesis, increased degenerate germ cells in seminiferous tubule and sperm morphological abnormalities versus controls more clearly than exposure to cis-permethrin alone, the expected potentiation of toxicity was not evident.