Pyrethroids are a class of widely used insecticides. Our recent epidemiological study of Chinese women reported that pyrethroid exposure was positively associated with the risk of primary ovarian insufficiency (POI). In this study, we utilized cypermethrin (CP), the most frequently detected pyrethroid in the environment, to recognize how lifelong and low-dose exposure to pyrethroids affects ovarian functions and the underlying mechanism(s). Female mice were exposed to CP at doses of human dietary intake of 6.7 μg/kg/day, an acceptable daily intake (ADI) of 20 μg/kg/day, or the chronic reference dose (RfD) of 60 μg/kg/day, starting from gestational day 0.5 until 44-week-old. We assessed effects on fertility, serum hormone levels, ovarian follicular development and ovarian transcriptomic profiles. Chronic exposure to CP at doses of ADI and RfD caused a significant reduction in the size of the primordial follicle pool on postnatal day (PND) 5 and the number of all types of follicles in 44-week-old mice, lower estrogen and higher gonadotropin levels, as well as decreased fertility. Significant increase in apoptosis and decrease in cell proliferation were observed in CP-exposed ovarian follicles from PND 5 and 44-week-old mice. Ovarian transcriptomic data showed that the pro-apoptotic protein BMF and the cell cycle inhibitor p27 were significantly up-regulated in CP-exposed ovaries. Cyp17a1, Cyp19a1 and Hsd17b1 genes involved in the key steps of steroidogenesis were down-regulated in the ovaries of female mice exposed to CP. This study first reported that lifelong exposure to CP at doses of ADI or RfD caused an ovarian phenotype similar to human POI in female mice and provided a mechanistic explanation. Our findings suggest that lifelong exposure to pyrethroids of low doses, which are recommended as ‘safe’ dosages, may have a significant impact on the ovarian health of female mammals and humans.

In developing countries, urban areas may be at greater risk of pesticide exposure compared to semi-urban agricultural regions. To investigate this, concentrations of selected pesticides were measured in 81 human milk samples collected in urban Kolkata and semi-urban Nadia in West Bengal, India. Three classes of pesticides were investigated – legacy organochlorines and emerging pyrethroids and neonicotinoids. The average concentration of the majority of the chemicals (DDT, its metabolites, HCH isomers, bifenthrin, endosulfan), showed a clear urban > semi-urban trend. Compared with previous measurements in other Indian cities and developing nations, current HCH and DDT concentrations in urban Kolkata were high. These chemicals were detected in 100% of the samples in both the urban and the semi-urban region. Also in both regions, the Estimated Daily Intake of DDTs, HCHs, aldrin, dieldrin and the pyrethroid bifenthrin for breastfed infants exceeded the Tolerable Daily Intake in a number of samples. Three pyrethroids were detected in human milk samples in India for the first time. This indicates a shift in the usage pattern of pesticides in India from organochlorines to pyrethroids. These findings may be used to drive targeted regulation of pesticides in developing countries with similar histories of pesticide use.

Pyrethroids are a class of the most commonly used insecticides. The urinary metabolites are usually used as biomarkers of pyrethroid exposures in humans. In this study, the temporal variability of urinary pyrethroid biomarkers was investigated among 114 Chinese young-aged adults who provided up to 4–11 urine samples over one year. The detection rates of four urinary pyrethroid biomarkers, 3-phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F-3PBA), trans-2,2-(dichloro)-2-dimethylvinylcyclopropane carboxylic acid (trans-DCCA) and cis-2,2-(dichloro)-2-dimethylvinylcyclopropane carboxylic acid (cis-DCCA) were 100%, 8%, 69% and 44%, respectively. The intraclass correlation coefficient (ICC) estimates for 3PBA indicated poor reproducibility (<0.15) in the spot urine samples of young-aged adults over a week, month and year. Log-transformed 3PBA used the least number of random spot urine samples (≥4) per person, which would provide a reliable biomarker estimate (ICC≥0.40) over a year. As the predictors of the top 33% yearly average 3PBA concentrations, the sensitivity and specificity of 3PBA ranged from 0.25 to 0.89, 0.58 to 0.96, respectively. Based on the results of this study, we recommend at least 4 urine samples collected 3 months apart for prospective assessment of pyrethroid exposure in the epidemiological studies to estimate exposure-response relationships between pyrethroids and health outcomes with relative long-term exposure periods.

Several populations of the amphipod, Hyalella azteca, have developed resistance to pyrethroid insecticides due to non-target exposure, but the dominance of the resistance trait is unknown. The current study investigated the dominance level of point mutations in natural populations of insecticide-resistant H. azteca and determined whether H. azteca from different clades with and without resistant alleles can hybridize and produce viable offspring. A parent generation (P₀) of non-resistant homozygous wild type H. azteca was crossbred with pyrethroid-resistant homozygous mutant animals and the tolerance of the filial 1 (F₁) generation to the pyrethroid insecticide, permethrin, was measured. Then the genotypes of the F₁ generation was examined to assure heterozygosity. The resistant parents had permethrin LC₅₀ values that ranged from 52 to 82 times higher than the non-resistant animals and both crossbreeding experiments produced heterozygous hybrid offspring that had LC₅₀ values similar to the non-resistant H. azteca parent. Dominance levels calculated for each of the crosses showed values close to 0, confirming that the L925I and L925V mutations were completely recessive. The lack of reproduction by hybrids of the C x D breeding confirmed that these clades are reproductively isolated and therefore introgression of adaptive alleles across these clades is unlikely. Potential evolutionary consequences of this selection include development of population bottlenecks, which may arise leading to fitness costs and reduced genetic diversity of H. azteca.

Pyrethroids are an important class of insecticides, and thousands of tons of these compounds are used in the United States every year. This study characterized exposures to pyrethroids and assessed demographic, socioeconomic, and lifestyle factors that modulate pyrethroid exposure using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2012, a nationally representative survey of the non-institutionalized population of the United States. Urinary levels of commonly used biomarkers of pyrethroid exposure, including 3-phenoxybenzoic acid (3-PBA), 4-fluoro-3-phenoxybenzoic acid (F-PBA), and cis-dibromovinyl-dimethylcyclopropane carboxylic acid (DBCA), were determined by liquid chromatography-tandem mass spectrometry. The detection rate of 3-PBA, a nonspecific metabolite of several pyrethroids, was 78.1% in adults (N = 5233) and 79.3% in children (N = 2295). The detection rates of all other pyrethroid metabolites were <10%. The median urinary level of 3-PBA in adults was 0.47 μg/L (interquartile range, 0.14–1.22 μg/L). For children, the median urinary level was 0.49 μg/L (interquartile range, 0.17–1.29 μg/L). Age, gender, family income-to-poverty ratio (PIR), levels of physical activity, alcohol intake, and body mass index were associated with 3-PBA levels in adults. In children, age, gender, race/ethnicity, and PIR were associated with 3-PBA levels. 3-PBA levels also differed significantly across NHANES cycles, with higher levels observed in NHANES 2011–2012. Geometric mean 3-PBA levels in U.S. adults were 0.41 μg/L in NHANES 2007–2008, 0.41 μg/L in NHANES 2009–2010, and 0.66 μg/L in NHANES 2011–2012. In U.S. children, geometric mean 3-PBA levels were 0.40 μg/L in NHANES 2007–2008, 0.46 μg/L in NHANES 2009–2010, and 0.70 μg/L in NHANES 2011–2012. These results demonstrate that pyrethroid exposures remain a current environmental health concern and lay the foundation for further preclinical and epidemiological studies assessing human health risks associated with pyrethroids.

Pyrethroids, a class of ubiquitous insecticides, have been recognized as endocrine-disrupting chemicals (EDCs). A lot of studies have implied the endocrine-disrupting effects of pyrethroids on the hypothalamic-pituitary-gonadal (HPG) axis. However, there are few review articles regarding the effects of pyrethroids on the HPG axis of mammal and human, especially new research progress made in this area. The present review sums up the effects of pyrethroids on the HPG axis-related reproductive outcomes, including epidemiological investigations based on human biomonitoring, animal studies and in vitro tests. Mechanisms have described that the endocrine-disrupting effects of pyrethroids on mammal can be mediated via the interaction with steroid receptors, the direct action on ion channels and signaling molecules. Finally, we summarize the current research gaps and suggest future directions in this topic.

Pyrethroid-resistant Hyalella azteca with voltage-gated sodium channel mutations have been identified at multiple locations throughout California. In December 2013, H. azteca were collected from Mosher Slough in Stockton, CA, USA, a site with reported pyrethroid (primarily bifenthrin and cyfluthrin) sediment concentrations approximately twice the 10-d LC50 for laboratory-cultured H. azteca. These H. azteca were shipped to Southern Illinois University Carbondale and have been maintained in pyrethroid-free culture since collection. Even after 22 months in culture, resistant animals had approximately 53 times higher tolerance to permethrin than non-resistant laboratory-cultured H. azteca. Resistant animals held in culture also lacked the wild-type allele at the L925 locus, and had non-synonymous substitutions that resulted in either a leucine-isoleucine or leucine-valine substitution. Additionally, animals collected from the same site nearly three years later were again resistant to the pyrethroid permethrin. When resistant animals were compared to non-resistant animals, they showed lower reproductive capacity, lower upper thermal tolerance, and the data suggested greater sensitivity to, 4, 4′-dichlorodiphenyltrichloroethane (DDT), copper (II) sulfate, and sodium chloride. Further testing of the greater heat and sodium chloride sensitivity of the resistant animals showed these effects to be unrelated to clade association. Fitness costs associated with resistance to pyrethroids are well documented in pest species (including mosquitoes, peach-potato aphids, and codling moths) and we believe that H. azteca collected from Mosher Slough also have fitness costs associated with the developed resistance.

California's Stream Pollution Trends program (SPoT) assesses long-term water quality trends, using 100 base-of-the-watershed sampling sites. Annual statewide sediment surveys from 2008 to 2012 identified consistent levels of statewide toxicity (19%), using the freshwater amphipod Hyalella azteca. Significant contaminant trends included a decrease in PCBs, stable concentrations of metals and PAHs, and a statewide increase in detections and concentrations of pyrethroid pesticides. The pyrethroid pesticide bifenthrin was detected in 69% of samples (n = 410). Detection of toxicity increased in a subset of samples tested at a more environmentally relevant test temperature (15 °C), and the magnitude of toxicity was much greater, indicating pyrethroid pesticides as a probable cause. Pyrethroid toxicity thresholds (LC50) were exceeded in 83% of samples with high toxicity. Principal components analysis related pyrethroids, metals and total organic carbon to urban land use.

The dynamic flux of an organophosphate and four pyrethroid pesticides was determined in an air-(soil)-water-sediment system based on monitoring data from Guangzhou, China. The total air–water flux, including air–water gaseous exchange and atmospheric deposition, showed deposition from air to water for chlorpyrifos, bifenthrin and cypermethrin, but volatilization for lambda-cyhalothrin and permethrin. The transport of the pesticides from overlying water to sediment suggested that sediment acted as a sink for the pesticides. Additionally, distinct annual atmospheric depositional fluxes between legacy and current-use pesticides suggested the role of consumer usage in their transport throughout the system. Finally, pesticide toxicity was estimated from annual air–water-sediment flux within an urban stream in Guangzhou. A dynamic flux-based risk assessment indicated that inter-compartmental transport of chlorpyrifos decreased its atmospheric exposure, but had little influence on its aquatic toxicity. Instead, water-to-sediment transport of pyrethroids increased their sediment toxicity, which was supported by previously reported toxicity data.

Chronic exposure to pyrethroid insecticides can result in strong selective pressures on non-target species in aquatic systems and drive the evolution of resistance and population-level changes. Characterizing the underlying mechanisms of resistance is essential to better understanding the potential consequences of contaminant-driven microevolution. The current study found that multiple mechanisms enhance the overall tolerance of Hyalella azteca to the pyrethroid permethrin. In H. azteca containing mutations in the voltage-gated sodium channel (VGSC), both adaptation and acclimation played a role in mitigating the adverse effects of pyrethroid exposures. Pyrethroid resistance is primarily attributed to the heritable mutation at a single locus of the VGSC, resulting in reduced target-site sensitivity. However, additional pyrethroid tolerance was conferred through enhanced enzyme-mediated detoxification. Cytochrome P450 monooxygenases (CYP450) and general esterases (GE) significantly contributed to the detoxification of permethrin in H. azteca. Over time, VGSC mutated H. azteca retained most of their pyrethroid resistance, though there was some increased sensitivity from parent to offspring when reared in the absence of pyrethroid exposure. Permethrin median lethal concentrations (LC50s) declined from 1809 ng/L in parent (P₀) individuals to 1123 ng/L in the first filial (F₁) generation, and this reduction in tolerance was likely related to alterations in acclimation mechanisms, rather than changes to target-site sensitivity. Enzyme bioassays indicated decreased CYP450 and GE activity from P₀ to F₁, whereas the VGSC mutation was retained. The permethrin LC50s in resistant H. azteca were still two orders-of-magnitude higher than non-resistant populations indicating that the largest proportion of resistance was maintained through the inherited VGSC mutation. Thus, the noted variation in tolerance in H. azteca is likely associated with inducible traits controlling enzyme pathways. A better understanding of the mechanistic and genomic basis of acclimation is necessary to more accurately predict the ecological and evolutionary consequences of contaminant-driven change in H. azteca.