Alteration of hepato-lipidomic homeostasis in A/J mice fed an environmentally relevant PFAS mixture.

In the present study, we have investigated liver lipid homeostasis and corresponding changes in transcript and functional product levels in A/J mice exposed to environmental relevant concentration of per- and polyfluoroalkyl substances (PFAS) mixture. Mice were fed environmentally relevant concentrations of a PFAS mixture during a period of 10 weeks. The concentrations of the 8 individual PFAS in the mixture were chosen based on measured concentrations in earthworms at a Norwegian skiing area. Our data show high liver accumulation of ∑PFAS in exposed mice, which paralleled significant elevation in body weight and hepatosomatic index (HSI) of male mice. UPC2 -MS/MS analysis in both positive and negative mode, respectively, indicated significant differences between control and exposure groups in the liver of exposed mice. Principal component analysis (PCA) of the features revealed separation of control and exposure groups in both sexes. From the significantly differential 207 lipids, only 72 were identified and shown to belong to eight different lipid classes. PCA of fatty acids (FAs) profile showed a clear separation between control and PFAS exposure groups in both female and male mice, with differential abundant levels of 5 and 4 hydrolyzed FAs, respectively. Transcript and protein analysis of genes associated with lipid homeostasis (ppar-α and ß, lxr-α and ß, rxr, fasn and srebp) showed that PFAS exposure produced sex- and individual response related alterations. Glutathione reductase (Gr) activity showed exposure-related changes in both female and male mice, compared with controls. Overall, the present study has demonstrated changes in lipid metabolism after PFAS exposure, showing that PFAS accumulation in the liver resulted to hepatotoxic effects, potential interference with membrane lipid profile and homeostasis, and oxidative stress. Given the structural similarity with FAs, interaction between PFAS and nuclear receptors such as PPARs may have severe consequences for general health and physiology in exposed animals and humans.

Effects of an environmentally relevant PFAS mixture on dopamine and steroid hormone levels in exposed mice.

In the present study, we investigated the dopaminergic and steroid hormone systems of A/J mice fed environmentally relevant concentrations of a perfluoroalkyl substance (PFAS) mixture over a period of 10 weeks. The PFAS mixture was chosen based on measured PFAS concentrations in earthworms at a Norwegian skiing area (Trondheim) and consisted of eight different PFAS. Dietary exposure to PFAS led to lower total brain dopamine (DA) concentrations in male mice, as compared to control. On the transcript level, brain tyrosine hydroxylase (th) of PFAS exposed males was reduced, compared to the control group. No significant differences were observed on the transcript levels of enzymes responsible for DA metabolism, namely - monoamine oxidase (maoa and maob) and catechol-O methyltransferase (comt). We detected increased transcript level for DA receptor 2 (dr2) in PFAS exposed females, while expression of DA receptor 1 (dr1), DA transporter (dat) and vesicular monoamine transporter (vmat) were not affected by PFAS exposure. Regarding the steroid hormones, plasma and muscle testosterone (T), 11-ketotestosterone (11-KT) and 17ß-estradiol (E2) levels, as well as transcripts for estrogen receptors (esr1 and esr2), gonadotropin releasing hormone (gnrh) and aromatase (cyp19) were unaltered by the PFAS treatment. These results indicate that exposure to PFAS doses, comparable to previous observation in earthworms at a Norwegian skiing area, may alter the dopaminergic system of mice with overt consequences for health, general physiology, cognitive behavior, reproduction and metabolism.

Perinatal exposure to a human relevant mixture of persistent organic pollutants: Effects on mammary gland development, ovarian folliculogenesis and liver in CD-1 mice.

The ability of persistent organic pollutants (POPs) with endocrine disrupting properties to interfere with the developing reproductive system is of increasing concern. POPs are transferred from dams to offspring and the high sensitivity of neonates to endocrine disturbances may be caused by underdeveloped systems of metabolism and excretion. The present study aimed to characterize the effect of in utero and lactational exposure to a human relevant mixture of POPs on the female mammary gland, ovarian folliculogenesis and liver function in CD-1 offspring mice. Dams were exposed to the mixture through the diet at Control, Low or High doses (representing 0x, 5000x and 100 000x human estimated daily intake levels, respectively) from weaning and throughout mating, gestation, and lactation. Perinatally exposed female offspring exhibited altered mammary gland development and a suppressed ovarian follicle maturation. Increased hepatic cytochrome P450 enzymatic activities indirectly indicated activation of nuclear receptors and potential generation of reactive products. Hepatocellular hypertrophy was observed from weaning until 30 weeks of age and could potentially lead to hepatotoxicity. Further studies should investigate the effects of human relevant mixtures of POPs on several hormones combined with female reproductive ability and liver function.