Toxicity of bisphenol analogues on the reproductive, nervous, and immune systems, and their relationships to gut microbiome and metabolism: insights from a multi-species comparison.

Bisphenols are common chemicals found in plastics and epoxy resins. Over the past decades, many studies have shown that bisphenol A (BPA) is a potential endocrine-disrupting chemical that may cause multisystem toxicity. However, the relative safety of BPA analogues is a controversial subject. Herein, we conducted a review of the reproductive toxicity, neurotoxicity, immunotoxicity, metabolic toxicity and gut microbiome toxicity of the BPA analogues in various species, including Caenorhabditis elegans, zebrafish, turtles, sheep, rodents, and humans. In addition, the mechanisms of action were discussed with focus on bisphenol S and bisphenol F. It was found that these BPA analogues exert their toxic effects on different organs and systems through various mechanisms including epigenetic modifications and effects on cell signaling pathways, microbiome, and metabolome in different species. More research is needed to study the relative toxicity of the lesser-known BPA analogues compared to BPA, both systemically and organ specifically, and to better define the underlying mechanisms of action, in particular, the potentials of disrupting microbiome and metabolism.

Gut microbiome in neuroendocrine and neuroimmune interactions: The case of genistein.

The healthy and diverse microbes living in our gut provide numerous benefits to our health. It is increasingly recognized that the gut microbiome affects the host's neurobehavioral state through production of metabolites, modulation of intestinal immunity (e.g., cytokines) and other mechanisms (e.g., gut neuropeptides). By sending the sensed information (e.g., metabolic and immunologic mediators) about the state of the inner organs to the brain via afferent fibers, the vagus nerve maintains one of the connections between the brain and GI tract, and oversees many critical bodily functions (e.g., mood, immune response, digestion and heart rate). The microbiota-gut-brain axis is a bidirectional communication between the gut, its microbiome, and the nervous system. In the present review, the roles of microbiome in neuroendocrine and neuroimmune interactions have been discussed using naturally occurring isoflavones, particularly the phytoestrogen genistein, as there are sex differences in the interactions among the microbiome, hormones, immunity and disease susceptibility. A deep understanding of the mechanisms underlying the interactions among the endocrine modulators, brain, endocrine glands, gut immune cells, vagus nerve, enteric nervous system and gut microbiome will provide important knowledges that may ultimately lead to treatment and prevention of debilitating disorders characterized by deficits of microbiome-neuroendocrine-neuroimmune relationships.

Survey of Meat Collected from Commercial Broiler Processing Plants Suggests Low Levels of Semicarbazide Can Be Created during Immersion Chilling.

ABSTRACT: Semicarbazide (SEM) is routinely employed as an indicator for the use of nitrofurazone, a banned antimicrobial. The validity of SEM as a nitrofurazone marker has been scrutinized because of other possible sources of the compound. Nonetheless, a U.S. trade partner rejected skin-on chicken thighs because of SEM detection and suspected nitrofurazone use. Because nitrofurazone has been banned in U.S. broiler production since 2003, we hypothesized that incidental de novo SEM formation occurs during broiler processing. To assess this possibility, raw leg quarters were collected from 23 commercial broiler processing plants across the United States and shipped frozen to our laboratory, where liquid chromatography-mass spectrometry was used to quantitatively assess for SEM. Leg quarter samples were collected at four points along the processing line: hot rehang (transfer from the kill line to the evisceration line), prechill (before the chilling process), postchill (immediately following chilling), and at the point of pack. Thigh meat with skin attached was removed from 535 leg quarters and analyzed in triplicate for SEM concentrations. The concentrations ranged from 0 to 2.67 ppb, with 462 (86.4%) of 535 samples below the regulatory decision level of 0.5 ppb of SEM. The 73 samples over the 0.5-ppb limit came from 21 plants; 53 (72.6%) of positive samples were in meat collected after chilling (postchill or point of pack). The difference in both prevalence and concentration of SEM detected before and after chilling was highly significant (P < 0.0001). These data support our hypothesis that SEM detection in raw broiler meat is related to de novo creation of the chemical during processing.

Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets.

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Developmental toxicity of bisphenol S in Caenorhabditis elegans and NODEF mice.

The growing concern surrounding bisphenol A (BPA) has led to increased industrial production and application of its analog bisphenol S (BPS). The goals of this study were: (1) To examine the generational effects in the nematode C. elegans for up to three generations following developmental exposure to BPS (0.1, 1.0, 5.0 and 10.0 µM), and (2) To examine the neurotoxicity and metabolic toxicity in NODEF mouse offspring exposed to BPS (3 µg/kg BW) in utero throughout gestation once/day via oral pipette. First, worms were exposed to BPS developmentally for a single period of 48 hours and then propagated for 2 additional generations. Exposure to 0.1 and 1.0 µM BPS decreased lifespan and the number of progeny with an ability to recover in subsequent generations. In contrast, worms exposed to 5.0 or 10.0 µM BPS exhibited a continuous effect in the second generation, e.g., decreased lifespan and reduced number of progeny. Only worms exposed to 10.0 µM BPS continued to have a significant long-term effect (e.g., decreased lifespan) through the third generation. In addition, worms developmentally exposed to BPS at 5.0 µM and 10.0 µM also showed decreases in body bends. In contrast, worms exposed to 0.1 µM BPS exhibited a significant increase in head thrashes. When the multigenerational effects were examined by exposing worms to BPS for 48 hours developmentally at each generation for three generations, an accumulative effect was observed in worms treated with 0.1 or 1.0 µM BPS for two generations, but not for three generations, suggesting a threshold existed. Worms exposed to either 5.0 or 10.0 µM BPS demonstrated accumulative effects through two and three generations. When the developmental effects of BPS were studied in NODEF mice, offspring exposed gestationally exhibited behavioral deficits at 12, but not at 3, weeks of age. Specifically, female offspring had decreases in working and short-term memories while male offspring showed increases in hyperactivity and anxiety-like behaviors. In summary, this study demonstrates the sex-related effects of BPS in NODEF mouse offspring exposed in utero, along with the generational effects observed in C. elegans.