Maternal exposure of mice to glyphosate induces depression- and anxiety-like behavior in the offspring via alterations of the gut-brain axis.

The past decade has been characterized by increased awareness and de-stigmatization of mental health issues, in particular the most common neuropsychiatric disorders depression and anxiety. Further, with growing understanding of neurodevelopmental disorders such as attention deficit and hyperactivity disorder and autism spectrum disorder, the number of diagnosed patients has increased. The pathogenesis of these behavioral disorders is multifactorial and early-life exposure to environmental chemicals has been proposed to be a relevant risk factor that might mediate these effects by disturbances on the gut-brain-axis. However, for glyphosate, the most widely used pesticide worldwide, there are only limited and inconsistent findings that link chronic low-dose exposure in particular during early life to neurobehavioral disorders. Here, we explored the impact of maternal oral glyphosate exposure (0.5 and 50 mg/kg body weight/day) during pregnancy and the lactational period on offspring's behavior, brain gene expression and gut microbiota using a cross-generational mouse model. Behavioral analyses revealed a depression- and anxiety-like behavior as well as social deficits most notably in adult female offspring of glyphosate-exposed dams. Furthermore, the expression of tryptophan hydroxylase 2, an enzyme discussed to be linked to behavioral problems, was reduced in the hippocampus of female offspring and correlated to a glyphosate-induced DNA hypermethylation of the gene. Moreover, maternal glyphosate exposure significantly altered the gut microbiota in the female offspring including a decreased abundance of Akkermansia and increased abundance of Alistipes and Blautia, bacteria involved in tryptophan metabolism and associated with depression- and anxiety-like disorders. Our results suggest that glyphosate might influence the gut-brain axis crosstalk following in-utero and lactational exposure. This study underlines the importance of understanding the impact of exposure to pesticides on the gut-brain axis and further emphasizes the need for microbiome analyses to be compulsorily included in health risk assessments of pesticides.

Wood emissions and asthma development: Results from an experimental mouse model and a prospective cohort study.

BACKGROUND: Increased use of renewable resources like sustainably produced wood in construction or for all sorts of long-lived products is considered to contribute to reducing society's carbon footprint. However, as a natural, biological material, wood and wood products emit specific volatile organic compounds (VOCs). Therefore, the evaluation of possible health effects due to wood emissions is of major interest. OBJECTIVES: We investigated the effects of an exposure to multiple wood-related VOCs on asthma development. METHODS: A murine asthma model was used to evaluate possible allergic and inflammatory effects on the lung after short- or long-term and perinatal exposure to pinewood or oriented strand board (OSB). In addition, wood-related VOCs were measured within the German prospective mother-child cohort LINA and their joint effect on early wheezing or asthma development in children until the age of 10 was estimated by Bayesian kernel machine regression (BKMR) stratifying also for family history of atopy (FHA). RESULTS: Our experimental data show that neither pinewood nor OSB emissions even at high total VOC levels and a long-lasting exposure period induce significant inflammatory or asthma-promoting effects in sensitized or non-sensitized mice. Moreover, an exposure during the vulnerable time window around birth was also without effect. Consistently, in our mother-child cohort LINA, an exposure to multiple wood-related VOCs during pregnancy or the first year of life was not associated with early wheezing or asthma development in children independent from their FHA. CONCLUSION: Our findings indicate that emissions from wood and wood products at levels commonly occurring in the living environment do not exert adverse effects concerning wheezing or asthma development.

Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility to Rheumatoid Arthritis in Mice.

The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG1 and IgG2a level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were regulator of G-protein signaling 1 (rgs1), interleukin-7 receptor (il-7r) and CXC chemokine 4 (cxcr4), all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.

Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.

Analyzing the growth of fibrosarcoma lines derived from IL-1alpha-, IL-1beta- , or IL-1alphabeta-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1alpha and IL-1beta exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1alpha(-/-)beta-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1beta(comp) lines, IL-1alpha strengthens anchorage-independent growth, but both IL-1alpha and IL-1beta support drug resistance. Corresponding to the aggressive growth, IL-1beta(comp) cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated alpha(v)/beta3 and matrix metalloroteinase expression. Recruitment of myeloid cells requires IL-1beta but is regulated by IL-1alpha, because inflammatory chemokine and cytokine expression is stronger in IL-1alpha(-/-)beta(comp) than in IL-1(wt) lines. This regulatory effect of tumor-derived IL-1alpha is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1beta. Both sarcoma cell-derived IL-1alpha and IL-1beta promote tumor growth. However, IL-1alpha exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1beta initiates systemic inflammation.

Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction.

There is evidence that cell-associated IL-1 alpha supports immune response induction. Here we explored the impact of malignant cell-derived IL-1 on immunogenicity, immune response induction and tumor-induced immunosuppression using 3-methylcholanthrene-induced fibrosarcoma lines derived from wild-type (wt), IL-1 alpha-, IL-1 beta- or IL-1a beta-knockout (IL-1 alpha(-/-), IL-1 beta(-/-), IL-1 alphabeta(-/-)) C57BL6 mice. The wt, IL-1 alpha(-/-), IL-1 beta(-/-) and IL-1 alphabeta(-/-) fibrosarcoma lines express MHC class I molecules at a high level. The lines do not differ in their susceptibility toward NK cells, macrophages, and allogeneic CTL, or in their capacity as stimulators of an allogeneic response. However, IL-1 beta(-/-) tumors rarely grow in the syngeneic host, which is the consequence of a strong T helper and CTL response induction by IL-1 alpha-competent, IL-1 beta(-/-) tumors. On the other hand, IL-1 beta-competent, IL-1 alpha(-/-) tumors strongly assist CD11b(+)Gr-1(+) myeloid-derived suppressor cell and regulatory T cell expansion, which both suppress with high efficacy activated T helper cell proliferation and CTL lysis. In IL-1 alphabeta(-/-) tumors, the absence of IL-1 alpha becomes decisive, i.e. despite reduced suppressor cell recruitment, tumor growth was unimpaired due to inefficient immune response induction. Thus, sarcoma cell-derived IL-1 alpha and IL-1 beta do not act in concert. Induction of a strong immune response by IL-1 alpha demands therapeutic exploitation, which may become more efficient if systemic induction of immunosuppression by IL-1 beta can also be circumvented.