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.

Glyphosate differentially affects the allergic immune response across generations in mice.

Exposure to environmental pollutants via food, particularly during the prenatal and early postnatal periods, has been linked to adverse effects on the immune system. Among these pollutants, the widely used pesticide glyphosate has been associated with endocrine disruption, autism, and cancer. Occupational high exposure to glyphosate has also been shown to influence immune function and exacerbate allergic asthma. However, there are no studies investigating the effect of a common low-dose glyphosate exposure on the allergic immune response - neither directly nor across generations. We therefore explored the impact of oral low-dose glyphosate exposure (0.5 and 50 mg/kg body weight/day) on airway inflammation in dams (F0) and the offspring (F1 and F2 generations) using a murine multi-generational asthma model. While exposure to 50 mg/kg glyphosate induced a mild eosinophilic infiltration in the bronchoalveolar lavage and TH2 cytokine production in the dams, the F1 offspring developed a reduced immune response after maternal exposure to 0.5 mg/kg glyphosate. In particular, decreased lung inflammation, HDM-specific IgE levels, and asthma-relevant cytokine production were primarily observed in the female F1 offspring. However, not only the TH2 cytokines IL-13 and IL-5 but also the TH17 cytokine IL-17 and TH1 cytokine IFN-γ were reduced indicating a more general immunosuppressive function. Notably, the dampened immune response was no longer observed in the female F2 generation. Furthermore, female F1 offspring showed an increased abundance of bacteria in the gut, which have been associated with probiotic-mediated reduced allergic immune responses. Our results suggest a potential immunosuppressive effect of low-dose maternal glyphosate exposure in the F1 offspring that might be mediated by an altered microbiota composition. Further studies are needed to explore if this type of immune response modulation might also be associated with impairments in immune defense upon infectious diseases or even cancer pathology.

Effects of exposure to single and multiple parabens on asthma development in an experimental mouse model and a prospective cohort study.

Parabens are widely used preservatives present in consumer products like cosmetics and food. Although several epidemiological studies suggest that early-life exposure to parabens might alter the immune response and allergy risk in childhood, the evidence with respect to asthma is not clear. Therefore, we investigated the effect of paraben exposure on asthma development in mice and humans. Using a murine asthma model the experimental data show both, an asthma-reducing effect after direct exposure of adult mice to n-butyl paraben (nBuP) as well as an asthma-promoting effect after maternal exposure to ethyl paraben (EtP) in the female offspring. Interestingly, exposure of mice to a mixture of EtP and nBuP starting prenatally until the end of asthma induction in the adult offspring was without effect on allergic airway inflammation. In addition, parabens were determined within the German prospective mother-child cohort LINA and their single and mixture effect on asthma development in children within the first 10 years of life was estimated by logistic and Bayesian kernel machine regression (BKMR). Both approaches revealed no adverse effects of parabens on children's asthma development, neither when stratified for being at risk due to a positive family history of atopy nor when analysed separately for sex specificity. Therefore, we conclude that although single parabens might differentially impact asthma development, an adverse effect could not be seen in a multiple paraben exposure setting. Consequently, not only the time point of exposure but also multiple exposure scenarios to parabens should be considered in the evaluation of individuals' specific disease risk.

Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern?

Fungi represent one of the most diverse and abundant eukaryotes on earth. The interplay between mold exposure and the host immune system is still not fully elucidated. Literature research focusing on up-to-date publications is providing a heterogenous picture of evidence and opinions regarding the role of mold and mycotoxins in the development of immune diseases. While the induction of allergic immune responses by molds is generally acknowledged, other direct health effects like the toxic mold syndrome are controversially discussed. However, recent observations indicate a particular importance of mold/mycotoxin exposure in individuals with pre-existing dysregulation of the immune system, due to exacerbation of underlying pathophysiology including allergic and non-allergic chronic inflammatory diseases, autoimmune disorders, and even human immunodeficiency virus (HIV) disease progression. In this review, we focus on the impact of mycotoxins regarding their impact on disease progression in pre-existing immune dysregulation. This is complemented by experimental in vivo and in vitro findings to present cellular and molecular modes of action. Furthermore, we discuss hypothetical mechanisms of action, where evidence is missing since much remains to be discovered.

Free and Total Amino Acids in Human Milk in Relation to Maternal and Infant Characteristics and Infant Health Outcomes: The Ulm SPATZ Health Study.

Free amino acids (FAAs) are important regulators of key pathways necessary for growth, development, and immunity. Data on FAAs in human milk (HM) and their roles in infant development are limited. We investigated the levels of FAAs and total amino acids (TAA, i.e., the sum of conjugated amino acids and FAAs) in HM in relation to infant and maternal characteristics and immunological conditions. FAA and TAA levels in HM sampled at 6 weeks (n = 671) and 6 months (n = 441) of lactation were determined using high-performance liquid chromatography. Child growth was ascertained at 4-5 weeks and at 6-7 months of age. Child allergy and lower respiratory tract infections were assessed in the first years of life. Associations of amino acid (AA) levels in HM with child growth and health outcomes were determined by Spearman correlation and modified Poisson regression, respectively. Free glutamine, glutamate, and serine in 6-week HM positively correlated with infant weight gain in the first 4-5 weeks of age. Maternal pre-pregnancy weight and body mass index (BMI) were negatively correlated with free glutamine and asparagine in 6-week and 6-month HM and positively correlated with the sum of TAAs in 6-month HM, but significance was lost following confounder adjustment. Free glutamine was lower in 6-month HM of mothers with an allergy (either active or non-active). No consistent associations were found between FAAs in HM and child health outcomes. However, potential negative associations were observed between specific FAAs and the risk of food allergy. These results suggest that specific FAAs play a role in infant growth. Moreover, these findings warrant further investigations into the relation of FAAs in HM with infant health outcomes and maternal allergy.

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.

Improving Rehabilitative Care of Methamphetamine Users in Germany: The Expert's Perspective.

Methamphetamine is one of the most frequently used drugs worldwide. In Germany, methamphetamine use has greatly increased in recent years, presenting the rehabilitative treatment system with new challenges. In this study, we identified deficits and possibilities for optimization in the field of medical rehabilitation. A total of 39 interviews and two focus groups with experts along the treatment course of methamphetamine users were conducted. Our analyses indicate that methamphetamine users are more difficult to treat compared with patients who consume other drugs. They are more likely to be associated with problematic characteristics and behaviors than other rehabilitants. Several health care deficits were revealed: too short rehabilitation treatment, no specific or differentiated therapy concepts, lack of capacity for education and vocational training, lack of outpatient options, and insufficient facilities for parents and children. Findings indicate that inadequate rehabilitation is being provided for methamphetamine users in Germany, indicating a need to adapt treatment for this group.