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Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood. We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico. GLY and AMPA in urine samples collected at (Visit 1) and (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery completed gestation). Detection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 for GLY and 0.25 (3.06) and 0.20 for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null. Urine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case-control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA's persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295.

It is generally claimed that glyphosate kills undesired plants by affecting the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme, disturbing the shikimate pathway. However, the mechanisms leading to plant death may also be related to secondary or indirect effects of glyphosate on plant physiology. Moreover, some plants can metabolize glyphosate to aminomethylphosphonic acid (AMPA) or be exposed to AMPA from different environmental matrices. AMPA is a recognized phytotoxin, and its co-occurrence with glyphosate could modify the effects of glyphosate on plant physiology. The present review provides an overall picture of alterations of plant physiology caused by environmental exposure to glyphosate and its metabolite AMPA, and summarizes their effects on several physiological processes. It particularly focuses on photosynthesis, from photochemical events to C assimilation and translocation, as well as oxidative stress. The effects of glyphosate and AMPA on several plant physiological processes have been linked, with the aim of better understanding their phytotoxicity and glyphosate herbicidal effects.

Aminomethylphosphonic acid (AMPA) - one of glyphosate’s main metabolites - has been classified as persistent in soils, raising concern regarding the widespread use of glyphosate in agriculture and forestry. Glyphosate may have negative or neutral effects on soil biota, but no information is available on the toxicity of AMPA to soil invertebrates. Therefore our aim was to study the effect of AMPA on mortality and reproduction of the earthworm species Eisenia andrei using standard soil ecotoxicological methods (ISO). Field-relevant concentrations of AMPA had no significant effects on mortality in acute or chronic assays. Except at the highest concentration tested, a significant biomass loss was observed compared to controls in the chronic assay. The number of juveniles and cocoons increased with higher concentrations of AMPA applied, but their mean weights decreased. This mass loss indicates higher sensitivity of juveniles than adults to AMPA. Our results suggest that earthworms coming from parents grown in contaminated soils may have reduced growth, limiting their beneficial roles in key soil ecosystem functions. Nevertheless, further research is needed to better understand the mechanisms underlying the sublethal effects observed here.

The potential connection between exposure to glyphosate and glyphosate-based herbicides (GBHs) and breast cancer risk is a topic of research that is rapidly gaining the public’s attention due to the conflicting reports surrounding glyphosate’s potential carcinogenicity. In this review, we synthesize the current published biomedical literature works that have explored associations of glyphosate, its metabolite, aminomethylphosphonic acid (AMPA), and GBHs with breast cancer risk in humans and human cell-based models. Using PubMed as our search engine, we identified a total of 14 articles that were included in this review. In the four human studies, urinary glyphosate and/or AMPA were associated with breast cancer risk, endocrine disruption, oxidative stress biomarkers, and changes in DNA methylation patterns. Among most of the 10 human cell-based studies, glyphosate exhibited endocrine disruption, induced altered gene expression, increased DNA damage, and altered cell viability, while GBHs were more cytotoxic than glyphosate alone. In summary, numerous studies have shown glyphosate, AMPA, and GBHs to have potential carcinogenic, cytotoxic, or endocrine-disruptive properties. However, more human studies need to be conducted in order for more definitive and supported conclusions to be made on their potential effects on breast cancer risk.

Tenofovir disoproxil fumarate (TDF) is an oral prodrug and acyclic nucleotide analog of adenosine monophosphate that inhibits HIV-1 (HIV) reverse transcriptase. A growing subset of TDF-treated HIV+ individuals presented with acute renal failure, suggesting tenofovir-associated kidney-specific toxicity. Our previous studies using an HIV transgenic mouse model (TG) demonstrated specific changes in renal proximal tubular mitochondrial DNA (mtDNA) abundance. Nucleosides are regulated in biological systems via transport and metabolism in cellular compartments. In this study, the role(s) of organic anion transporter type 1 (OAT1) and multidrug-resistant protein type 4 (MRP4) in transport and regulation of tenofovir in proximal tubules were assessed. Renal toxicity was assessed in kidney tissues from OAT1 knockout (KO) or MRP4 KO compared with wild-type (WT, C57BL/6) mice following treatment with TDF (0.11 mg/day), didanosine (ddI, a related adenosine analog, 0.14 mg/day) or vehicle (0.1 M NaOH) daily gavage for 5 weeks. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. mtDNA abundance and ultrastructural pathology were analyzed. mtDNA abundance in whole kidneys from both KO and WT was unchanged regardless of treatment. Renal proximal tubular mtDNA abundance from OAT1 KO also remained unchanged, suggesting prevention of TDF toxicity due to loss of tenofovir transport into proximal tubules. In contrast, renal proximal tubules from MRP4 KO exhibited increased mtDNA abundance following TDF treatment compared with WT littermates, suggesting compensation. Renal proximal tubules from TDF-treated WT and MRP4 KO exhibited increased numbers of irregular mitochondria with sparse, fragmented cristae compared with OAT1 KO. Treatment with ddI had a compensatory effect on mtDNA abundance in OAT1 KO but not in MRP4 KO. Both OAT1 and MRP4 have a direct role in transport and efflux of tenofovir, regulating levels of tenofovir in proximal tubules. Disruption of OAT1 activity prevents tenofovir toxicity but loss of MRP4 can lead to increased renal proximal tubular toxicity. These data help to explain mechanisms of human TDF renal toxicity.

The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV). Biodegradable poly(lactide-co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ∼200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1∶50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1∶1 ratio of IC50 values. TFV combined with NP-SQV at a 1∶1 ratio of IC50 values also showed strong synergy (CI50 = 0.07). ARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities.

Four diphenyl pyrene-derived aminophosphonates were synthesized. Attempts were made to synthesize diphenyl N-(R)-α-methylbenzylamino(pyren-1-yl)methylphosphonate (3e) in order to obtain the chiral aminophosphonate bearing a pyrene moiety. Because these attempts failed, dimethyl and dibenzyl N-(R)-α-methylbenzyl substituted aminophosphonates 4 and 5 were synthesized and the predominant diastereoisomer of dimethyl aminophosphonate 4 was isolated. The resolution of the diastereomeric mixture of 5 failed. Aminophosphonates 3a–d and the predominant diastereoisomer of 4 were investigated in terms of their ecotoxicity using tests performed on the ostracode Heterocypris incongruens and the fluorescent bacterium Vibrio fisheri. The tests confirmed the moderate-to-high ecotoxicity of aminophosphonates 3a–d and 4, but no evident correlation between the structure and toxicity has been found.

The assessment of the direct impact of breakdown products of pesticide components on aquatic wildlife is ecotoxicologically relevant, but frequently disregarded. In this context, the evaluation of the genotoxic hazard posed by aminomethylphosphonic acid (AMPA-the major natural degradation product of glyphosate) to fish emerges as a critical but unexplored issue. Hence, the main goal of the present research was to assess the AMPA genotoxic potential to fish following short-term exposures (1 and 3 days) to environmentally realistic concentrations (11.8 and 23.6 μg L(-1)), using the comet and erythrocytic nuclear abnormalities (ENA) assays, as reflecting different levels of damage, i.e. DNA and chromosomal damage, respectively. Overall, the present findings pointed out the genotoxic hazard of AMPA to fish and, subsequently, the importance of including it in future studies concerning the risk assessment of glyphosate-based herbicides in the water systems.

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms.

Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia. (Clin Mol Hepatol 2018;24:339-344)