Associations of exposure to melamine, cyanuric acid, phthalates with markers of early kidney impairment, and their interactions in US adults: analyses of NHANES 2003-2004 data.

Melamine (MEL), cyanuric acid (CYA), and phthalates have kidney toxicity, respectively. Still, no study has explored whether there is an interaction of co-exposure to MEL, CYA, and phthalates on early kidney impairment, including cystatin C (CYST), beta 2-microglobulin (ß2-MG), albumin creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Urine samples were collected from 333 adults in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, and urinary MEL, CYA, and ten metabolites of phthalates were quantified. The multiple markers of early kidney impairment were also measured, including serum CYST, ß2-MG, urinary ACR, and eGFR. Their associations were explored by multiple linear and multivariate logistic regression models. Meanwhile, the interactions of co-exposure to MEL, CYA, and phthalates on early kidney impairment were analyzed by Wilcoxon rank-sum test combined with the LSD test. In the multiple linear regression model, urinary concentrations of monobenzyl phthalate (MBzP), mono(3-carboxypropyl) phthalate (MCPP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-ethylhexyl) phthalate (MEHP) were positively associated with urinary ACR, serum ß2-MG, and CYST, respectively. Urinary concentrations of MBzP and MCPP were negatively associated with eGFR. In the multivariate logistic regression model, increased urinary CYA concentration was the risk factor of CYST abnormality with an odds ratio (OR) (95% confidence interval, 95% CI) of 2.38 (1.01, 5.60) (P = 0.047) and increased urinary MBzP concentration was the risk factor of ACR abnormality with an OR of 2.59 (1.41, 4.75) (P = 0.002). The co-exposure to MEL, CYA, and four phthalate metabolites (MEHP, MBzP, MCPP, and MECPP) presented significantly interactive effects on the markers of early kidney impairment, respectively. There were the independent and interactive effects of exposure to MEL, CYA, and specific phthalate metabolites on early kidney impairment. Due to co-exposure to multiple environmental chemicals in our daily life, more attention should be paid to the health damage raised by the synergistic effects of environmental chemicals.

Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage.

Chemotherapeutic agents induce complex tissue responses in vivo and damage normal organ functions. Here we use the feather follicle to investigate details of this damage response. We show that cyclophosphamide treatment, which causes chemotherapy-induced alopecia in mice and man, induces distinct defects in feather formation: feather branching is transiently and reversibly disrupted, thus leaving a morphological record of the impact of chemotherapeutic agents, whereas the rachis (feather axis) remains unperturbed. Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine (Ara-C). Selective blockade of cell proliferation was seen in the feather branching area, along with a downregulation of sonic hedgehog (Shh) transcription, but not in the equally proliferative rachis. Local delivery of the Shh inhibitor, cyclopamine, or Shh silencing both recapitulated this effect. In mouse hair follicles, those chemotherapeutic agents that disrupted feather formation also downregulated Shh gene expression and induced hair loss, whereas doxorubicin or Ara-C did not. Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue, namely via the cell population-specific, Shh-dependent inhibition of proliferation. This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage.