Effects of Perinatal Exposure to Dibutyltin Chloride on Fat and Glucose Metabolism in Mice, and Molecular Mechanisms, in Vitro.

BACKGROUND: The organotin dibutyltin (DBT) is used in the manufacture of polyvinyl chloride (PVC) plastics, in construction materials, and in medical devices. Previous animal studies showed detrimental effects of DBT during in utero development at relatively high doses, but little was known about the effects of DBT exposure at environmentally relevant doses on endpoints such as obesity and metabolic disease. OBJECTIVES: We tested the potential obesogenic effects of DBT using in vitro and in vivo models. METHODS: We evaluated the effects of DBT on nuclear receptor activation and adipogenic potential using human and mouse multipotent mesenchymal stromal stem cells (MSCs). We also evaluated the effects of perinatal exposure to environmentally relevant doses of DBT in C57BL/6J mice. RESULTS: DBT activated human and mouse PPARγ and RXRα in transient transfection assays, increased expression of adipogenic genes, promoted adipogenic differentiation and increased lipid accumulation in mouse and human MSCs, in vitro. DBT-induced adipogenic differentiation was abolished by the PPARγ antagonist T0070907, indicating that DBT was acting primarily through PPARγ. Perinatal exposure to low doses of DBT led to increased fat storage, decreased glucose tolerance, and increased circulating leptin levels in male, but not female, mice. CONCLUSIONS: DBT acted as an obesogen by inducing lipid accumulation in human and mouse MSCs through a PPARγ-dependent pathway. In vivo exposure to biologically relevant doses of DBT during perinatal development led to increased fat storage, elevated leptin levels in plasma, and glucose intolerance in mice. Based on these findings, we posit that monitoring of DBT levels in human samples may aid in understanding and potentially preventing the rising rates of metabolic disorders in human populations. https://doi.org/10.1289/EHP3030.

Rapid evolution of symbiont-mediated resistance compromises biological control of aphids by parasitoids.

There is growing interest in biological control as a sustainable and environmentally friendly way to control pest insects. Aphids are among the most detrimental agricultural pests worldwide, and parasitoid wasps are frequently employed for their control. The use of asexual parasitoids may improve the effectiveness of biological control because only females kill hosts and because asexual populations have a higher growth rate than sexuals. However, asexuals may have a reduced capacity to track evolutionary change in their host populations. We used a factorial experiment to compare the ability of sexual and asexual populations of the parasitoid Lysiphlebus fabarum to control caged populations of black bean aphids (Aphis fabae) of high and low clonal diversity. The aphids came from a natural population, and one-third of the aphid clones harbored Hamiltonella defensa, a heritable bacterial endosymbiont that increases resistance to parasitoids. We followed aphid and parasitoid population dynamics for 3 months but found no evidence that the reproductive mode of parasitoids affected their effectiveness as biocontrol agents, independent of host clonal diversity. Parasitoids failed to control aphids in most cases, because their introduction resulted in strong selection for clones protected by H. defensa. The increasingly resistant aphid populations escaped control by parasitoids, and we even observed parasitoid extinctions in many cages. The rapid evolution of symbiont-conferred resistance in turn imposed selection on parasitoids. In cages where asexual parasitoids persisted until the end of the experiment, they became dominated by a single genotype able to overcome the protection provided by H. defensa. Thus, there was evidence for parasitoid counteradaptation, but it was generally too slow for parasitoids to regain control over aphid populations. It appears that when pest aphids possess defensive symbionts, the presence of parasitoid genotypes able to overcome symbiont-conferred resistance is more important for biocontrol success than their reproductive mode.

Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice.

Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants. This transgenerational inheritance has significant implications for understanding disease etiology. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and lactation predisposes unexposed F4 male descendants to obesity when dietary fat is increased. Analyses of body fat, plasma hormone levels, and visceral white adipose tissue DNA methylome and transcriptome collectively indicate that the F4 obesity is consistent with a leptin resistant, thrifty phenotype. Ancestral TBT exposure induces global changes in DNA methylation and altered expression of metabolism-relevant genes. Analysis of chromatin accessibility in F3 and F4 sperm reveals significant differences between control and TBT groups and significant similarities between F3 and F4 TBT groups that overlap with areas of differential methylation in F4 adipose tissue. Our data suggest that ancestral TBT exposure induces changes in chromatin organization transmissible through meiosis and mitosis.