Dechlorane 602 (Dec 602), a chlorinated flame retardant, has been widely detected in different environmental matrices and biota. However, toxicity data for Dec 602 seldom have been reported. A metabolomics study based on ultra-high performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry was employed to study the urine and sera metabolic profiles of mice administered with Dec 602 (0, 0.001, 0.1, and 10 mg/kg body weight per day) for 7 days. A significant difference in metabolic profiling was observed between the Dec 602 treated group and the control group by multivariate analysis, which directly reflected the metabolic perturbations caused by Dec 602. The metabolomics analyses of urine from Dec 602-exposed animals exhibited an increase in the levels of thymidine and tryptophan as well as a decrease in the levels of tyrosine, 12,13-dihydroxy-9Z-octadecenoic acid, 2-hydroxyhexadecanoic acid and cuminaldehyde. The metabolomics analyses of sera showed a decrease in the levels of kynurenic acid, daidzein, adenosine, xanthurenic acid and hypoxanthine from Dec 602-exposed animals. These findings indicated Dec 602 induced disturbance in phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism, tyrosine metabolism, pyrimidine metabolism, purine metabolism, ubiquinone and other terpenoid-quinone biosynthesis; phenylalanine metabolism and aminoacyl-tRNA biosynthesis. Significant alterations of immune and neurotransmitter-related metabolites (tyrosine, tryptophan, kynurenic acid, and xanthurenic acid) suggest that the toxic effects of Dec 602 may contribute to its interactions with the immune and neuronal systems. This study demonstrated that the UHPLC-ESI-IT-TOF-MS-based metabolomic approach can obtain more specific insights into the potential toxic effects of Dec 602 at molecular level.

Isoflavones (ISOs) are naturally occurring endocrine-disrupting compounds. Few human studies have evaluated the effects of ISO exposure on neonatal anthropometry. This study aimed to examine the associations of maternal soy product consumption and urinary ISO concentrations, including genistein, daidzein, glycitein, and equol, with neonatal anthropometry, based on a Chinese cohort study. In Shanghai-Minhang Birth Cohort Study, pregnant women at 12–16 weeks of gestation were recruited, and they completed a structured questionnaire to assess soy product consumption during pregnancy. They also provided a single spot urine sample for the ISO assay. Neonatal anthropometric indices (birth weight; arm, waist, and head circumference; and triceps, back, and abdominal skinfold thickness) were measured at birth. Multivariable linear regression analysis was performed among the 1188 mother-infant pairs to examine the associations between maternal soy product consumption and neonatal anthropometry. The same statistical model was applied to examine the associations between maternal ISO exposure and neonatal anthropometry among 480 mother-infant pairs. Neonate girls born to mothers who “sometimes” and “frequent” consumed soy products had 169.1 g (95% confidence interval [CI], −68.9–407.1) and 256.5 g (95% CI, 17.1–495.8) higher birth weight, respectively, than those born to mothers who “never” consumed soy products during pregnancy. We observed consistent associations between higher maternal urine ISO concentrations and increased anthropometric indices (birth weight, arm and waist circumference, and triceps and abdominal skinfold thickness) in neonate girls, while no association was observed among boys. The findings suggested that maternal dietary ISO intake during pregnancy is associated with fetal development in a sex-specific pattern. In addition, follow-up studies are required to evaluate whether the observed changes in anthropometric indices at birth are associated with health conditions later in life.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and several other environment/food-borne toxic compounds induce their toxicity via the aryl hydrocarbon receptor (AhR). AhR is also modulated by various endogenous ligands e.g. highly potent tryptophan (Trp)-derivative FICZ (6-formylindolo[3,2-b]carbazole) and natural ligands abundant in the human diet e.g. polyphenols. Therefore, evaluating AhR species-specific responses is crucial for understanding AhR physiological functions, establishing risk assessments, and exploring the applicability of AhR mediators in drug and food industry towards human-based usages. We studied AhR transactivation of FICZ/TCDD in vitro in a time-dependent and species-specific manner using dioxin responsive luciferase reporter gene assays derived from rat (DR-H4IIE) and human (DR-HepG2) hepatoma cells. We observed for the first time that FICZ potency was similar in both cell lines and was 40 times higher than TCDD in DR-HepG2 cells. Depleting Trp-derivative endogenously produced ligands by using culture medium without Trp, resulted in 3-fold higher AhR activation upon adding FICZ in DR-H4IIE cells, in contrast to DR-HepG2 cells which revealed a fast degradation of FICZ induction from 10 h post-exposure to complete disappearance after 24 h. Seven polyphenols and a mixture thereof, chosen based on commercially recommended doses and adjusted to human realistic exposure, caused rat and human species-specific AhR responses. Two isoflavones (daidzein and genistein) induced rat AhR synergistic effects with FICZ and/or TCDD, while quercetin, chrysin, curcumin, resveratrol, and the mixture exerted a strong inhibitory effect on the human AhR. Strikingly, resveratrol and quercetin at their realistic nanomolar concentrations acted additively in the mixture to abolish human AhR activation induced by various TCDD concentrations. Taken together, these results illustrate the species-specific complexity of AhR transcriptional activities modulated by various ligands and highlight the need for studies of human-based approaches.

We evaluated the influence of the oil-related environmental contaminant benzene (0, 10, 100, or 1000 ng/mL) alone and in combination with apigenin, daidzein, or rutin (10 μg/mL each) on viability; proliferation (accumulation of proliferating cell nuclear antigen); apoptosis (accumulation of Bax); and release of progesterone (P), testosterone (T), and estradiol (E) in cultured porcine ovarian granulosa cells. Cell viability; proliferation; apoptosis; and release of P, T, and E have been analyzed by the trypan blue test, quantitative immunocytochemistry, and ELISA, respectively. Benzene did not affect apoptosis, but reduced ovarian cell viability and P and E release, and promoted proliferation and T output. Apigenin did not affect cell viability, but stimulated proliferation and T and E release, and inhibited apoptosis and P secretion. It prevented and reversed the action of benzene on proliferation and P and T release, and induced the inhibitory action of benzene on apoptosis. Daidzein promoted cell viability, proliferation, P release, but not apoptosis and T or E release. Daidzein induced the stimulatory effect of benzene on T, without modifying other effects. Rutin administered alone reduced cell viability and apoptosis, and promoted cell proliferation. Furthermore, rutin prevented and reversed the effect of benzene on proliferation and P and E release. These observations suggest the direct action of benzene and plant polyphenols on basic ovarian cell functions, and the ability of apigenin and rutin, but not of daidzein, to prevent benzene effects on the ovary.