Interestingly, many chemicals used by humans, which are not intended for use on microbial communities, have been shown to affect microbes. For example, caffeine, a common mental stimulant, alters biofilm respiration, and an antihistamine, diphenhydramine, has been demonstrated to modify the microbial community and respiration of lake biofilms. Because of unexpected pharmaceutical effects, it is relatively difficult to predict what will occur in model organisms. This problem is exacerbated by a lack of information regarding pharmaceuticals’ effects on terrestrial insects: no available publications report the effects on any terrestrial insects’ microbial community. Arthropods, such as insects and crustaceans, rely on hormones to grow, develop, mate and even produce pigmentation. However, many pharmaceuticals, especially hormones, resemble chemicals that these organisms rely on for growth and development. These pharmaceuticals then bind to receptors and either over-express or suppress their counterparts’ natural function. This has been reported in birds, reptiles, macetas redondas and arthropods where endocrine disruption occurs, primary and secondary sexual characteristics are modified, and courtship behaviors change.
While most arthropod hormones do not closely match those of mammals, their molting hormone , is very similar to 17β-estradiol . In crustaceans, mammalian hormones have been known to cause both increased molting events and inhibition of chitobiase, the enzyme responsible for digestion of the cuticle during insect molting. In insects, 17α-ethinylestradiol, a common synthetic birth control hormone, has been shown to alter molting and lead to deformities of C. riparius. Also, BisphenolA, a common plasticizer, can bind and activate estrogen receptors in humans, and the ecdysone-binding protein in insects. In addition to these effects, pharmaceuticals have been shown to cause effects to insects over multiple generations. Megaselia scalarisis a common saprophagous pest. They are known to infect living humans , provide important ecological roles as detritivores, and because they often feed on human corpses are commonly used in forensic entomology to determine time of death. This species will generally feed on a variety of decomposing plant and animal tissues, and acts as a vector of pathogens. These insects are both fecund and hardy because females can lay over 650 eggs in 16 days and are tolerant of heavy metals. The white, roughly football-shaped eggs, hatch after approximately 24 hours into white translucent larvae. When they have matured to third instar they pupariate. Their detritivorous larval life history exposes them to a wide diversity of microorganisms that may act as pathogens, commensals, and symbionts. There is currently no record of how M. scalaris acquires their microbiota or if any symbionts are required. However, it stands to reason that they, like so many other insects, would rely on microbial symbionts.
There are many ways insects acquire symbionts: from their diet, the environment, their social network, or vertical transmittance. Currently there is little to no information regarding pharmaceutical effects at the concentrations found in reclaimed water on the growth or microbial community composition of any terrestrial detritivore. These detritvores become exposed to contaminants after the CECs enter surface waters, soil, and plants from overflow and wastewater reuse. There are studies involving antibiotics at high doses to determine necessity of microbiota in several insects, but these have not tested relevant concentrations found in reclaimed water or joint effects of other pharmaceuticals, which often coexist with antibiotics. To assess potential effects of common pharmaceuticals, we used a series of bio-assays to determine the possibility of individual and joint contamination on development, mortality and population sex ratios of M. scalaris. Any effects would have potentially important implications from medical, ecological, and forensic perspectives. Also, as there is currently no information on M. scalaris’ microbial community, information generated from this study could serve as novel information into the role possible symbionts play in M. scalaris development. Test compounds included: acetaminophen, caffeine, three antibiotics, and four estrogenic steroidal hormones. Six treatments were examined: acetaminophen, caffeine, an antibiotic mixture , a hormone mixture , a mixture of all chemicals , and a control, consisting of only distilled water. Distilled water was tested for CECs and found to not contain any. Treatment groups were chosen as representative compounds for pain relievers, mental stimulants, antibiotics commonly used on humans and livestock, hormones normally either produced or prescribed to humans, and as a mixture that would be simple, yet representative of wastewater effluent or reclaimed wastewater. Artificial diets were prepared at room temperature to negate any decomposition of the CECs.
Acetaminophen , caffeine , estrone , 19-norethindrone , 17β- estradiol , 17α- ethynylestradiol , lincomycin , and oxytetracycline concentrations were chosen based on the maximum concentrations measured by Kolpin et al. 5 . Ciprofloxacin concentration was chosen from the maximum lake water concentration reported by Mutiyar and Mittal6 . The chemicals used were purchased as follows: acetaminophen with a purity of ≥ 90%; ; caffeine at laboratory grade purity ; lincomycin, oxytetracycline, and ciprofloxacin with purities of ≥98% ; estrone, 19-norethindrone, 17β- estradiol, and 17α- ethynylestradiol at ≥98% purity . Blue formula 4-24® instant Drosophila medium, hereafter known as ‘blue diet’, was purchased from Carolina Biological Supply Company . Hydrochloric acid was obtained from Fisher Scientific. Sodium hydroxide was acquired from Sigma-Aldrich as anhydrous pellets. Stock solutions were prepared by adding powdered chemicals to deionized water. Approximately 5 mL 80% ethanol was added to 250 mL steroidal hormone solutions to facilitate dissolution. Hydrochloric acid was added to antibiotic chemical solutions to facilitate dissolution and pH was adjusted using NaOH to pH 4.00. Compounds were added to distilled water to the desired concentrations for each treatment and then an equal amount of blue diet flakes was added as described by the manufacturer. In all experiments, preparations and concentrations of treatment groups were prepared as stated previously.Eggs were transferred, by microspatula, to the blue diet of each 9 cm Petri dish. There were 3 replicates per life stage for each of the 6 treatments . Lids contained a size 7 cork-borer hole affixed with 2 layers of fine organza mesh to allow for moisture and gas exchange. Following egg placement, Petri dish lids and bottoms were aligned and secured with parafilm. Petri dishes were monitored daily for development. Six individuals were collected at third instar, pupa, and adult life-stages,maceta de 10 litros triple washed with 200 proof ethanol, and stored in clean 200 proof ethanol at -60 °C until DNA extraction. During the collection of each treatment group and life-stage, blanks in triplicate of DDI H2O were used to monitor contamination. Before extraction, triplicate blanks were pooled. All genomic information was processed using macQIIME ver. 1.9.1-20150604 . We used USEARCH v6.1 to identify and remove chimeric sequences, and SUMACLUST to cluster OTUs and remove any with less than two reads per sample. We used 97% sequence identity to bin OTUs and choose representative OTUs. We then performed standard alpha and beta diversity analyses in QIIME. To assign taxonomy to OTUs, Greengenes taxonomy and the RDP Naïve Bayesian Classifier were utilized, and we also performed BLASTN searches against NCBI’s online Nucleotide Collection and 16S ribosomal RNA sequences databases . Taxonomy was then used to identify any mitochondria or chloroplast OTUs, which were removed from the dataset as in McFrederick & Rehan . We aligned the quality-filtered dataset using the pynast aligner and the Greengenes database . We then reconstructed the phylogeny of the bacterial OTUs using FASTTREE version 2.1.3. Next we performed weighted and unweighted UniFrac analyses using the generated phylogeny and OTU tables. Using the generated distance matrices, we performed Adonis and created PCA 74 graphs in R version 3.3.1 .
Foralpha diversity, we plotted rarefaction curves in GraphPad Prism version 6.00 software , and used gplots to create a heatmap of the most abundant bacterial families; a 0.025 proportional abundance in at least one sample was used as the cutoff.All statistical analyses were performed using R . Normality was determined using Shapiro-Wilk normality tests. Differences in days to pupariation were determined using the ‘survival’ and the ‘OIsurv’ packages. In all cases, when data were not considered normal, either a Poisson distribution or a negative binomial generalized linear model was used and the best fitting model was determined from Akaike’s ‘An Information Criterion’. Adonis within the R package “vegan” was used for all PERMANOVA analyses. As there is no post-hoc test for Adonis, we used adjusted p values obtained from metagenomeHIT_zig in R through QIIME to determine differentially abundant OTUs in treatments between life stages.Megaselia scalaris, a common detritivore, has been known to develop on substances as diverse as human wounds and corpses, modeling clay, and emulsion paint. Their ability to grow and mature on these diets, with minimal effect on their survival, and their tolerance to heavy metals 145 makes any effect of pharmaceuticals at very low doses found in reclaimed water even more surprising. In our study, the females had no preference for untreated diets versus any treated diets. This poses a problem for the insect population, as there was higher larval mortality when developing on a caffeinecontaminated food source. Because females require an additional 24 hours 142 afteremergence in order to be receptive to males, populations exposed to hormones or antibiotics would be adversely affected. If females require an extra six days to emerge and become receptive, there is a reasonable possibility the males would leave the area or perish before mating. In addition, the suitability of decaying food sources tends to be temporary . Collectively, these factors could likely negatively influence population growth. Also, these changes in population growth rate could hinder forensic scientists from determining an accurate time of death if there were long lasting or even moderate concentrations of these pharmaceuticals in the body at death. Sex ratios of emergent adults were also affected in the caffeine and mixture treatments. The sex ratios found in control treatments in our study are similar to those reported in Benner & Ostermeyer of a male: female sex ratio at 25° C of 1.18:1. However, sex ratios from the acetaminophen, caffeine, and mixture treatments differed significantly from the controls. A major difference in sex ratio would change the reproductive capacity of a population. It is unclear why acetaminophen and caffeine would alter sex ratios, however acetaminophen as been recorded to hinder the production of arachadonic acid in mosquitoes, another Dipteran, and it could be playing a similar role here . Ibuprofen, another analgesic and antipyretic has been shown to alter the sex ratio in another . Many insects rely on their microbial communities and endosymbionts to grow and develop . However, Adonis, the statistical method used to analyze these data, does not have a post hoc test available that would allow direct pairwise comparisons between treatments. Nonetheless, there are changes in the bacterial community based on adjusted p-values evaluating differential abundance. We found significant shifts in the microbial community in the various life stages examined within the control treatments. A similar result has been reported for mosquitoes and other insects. Not surprisingly, insects that undergo complete metamorphosis and also rely on a different food source as adults would require a different bacterial community; however there is one family, Pseudomonadaceae, which appears in all treatments and life-stages. Species in this family are gram-negative Proteobacteria that cannot survive in acidic environments . They are fairly common in insects , and can be responsible for 90+% of the bacterial community. They are resistant to antibiotics , which potentially explains why they are so prevalent in many of our treatments. Pseudomonadaceae is responsible for ~ 50% of the bacteria in all life-stages, followed by Alcaligenaceae, Enterobacteriaceae, and Xanthomonadaceae. Pseudomonadaceae and Enterobacteriaceae families contain known symbionts in insects and could be filling the same role in M. scalaris. When Pseudomonadaceae is removed from the heatmap , it becomes clear how the next three highly proportional families change with life-stage. Alcaligenaceae tends to become more proportionally abundant in pupae and adults than in larvae. Species in the family Alcaligenaceae are oxidase- and catalase-positive and utilize a variety of organic and amino acids as carbon sources . Enterobacteriaceae has higher proportions in larvae than in adults. Species of Enterobacteriaceae are likely to be either symbionts or a pathogen to their hosts . Enterobacteriaceae includes Buchnera, an important endosymbiont of aphids , and other species that inhabit various insects to provide facultative benefits.