We will study the effects of environmental heavy metals (Cd++, Hg++), pesticide 1,2-dibromo-3-chloropropane (DBCP) and herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on two types of biosignal transmission: 1) Phospholipid N-methylation in which two N-methyltransferases (PMT I and II) convert membrane phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by stepwise methylation in the presence of S-adenosyl-L-methionine. PMT I is the rate limiting enzyme in this process. The PMT system transducts information from surface receptors across the cell membrane. This system is irreversibly inhibited by Cd++ and Hg++. It is possible that the active metabolites of DBCP, epichlorohydrin and epibromohydrin, react covalently with PMTs. 2) In view of the structural similarity of phenoxyacetic acids and acetic acid, 2,4,5-T and related compounds may enter the acetylocholine (ACh) synthetic pathway through the formation of corresponding coenzymes (CoA) forming false cholinergic transmitters. Alternately, they may inhibit acetate thiokinase preventing the formation of ACoA and ACh in developing or regenerating tissues. This study has the following specific aims: 1) Inhibition of PMTs by CD++, Hg++ and Cu++. The PMTs include enzymes from rat diaphragm, kidney and liver, and human placental trophoblast. 2) Protective effects of Zn++, Mg++, cysteine and metallothionein against the inhibition of PMTs by Cd++. 3) Relation between the inhibition of PMT and functional activity of tissues treated with Cd++ and epihalohydrins (cholinergic transmission in rat hemidiaphragm, neutral amino acid uptake in human placental trophoblast). 4) Activities of PMT in tissues from rats that received 1,2-dibromo-3-chloropropane (DBCP). 5) Inhibition of the ACh synthetic pathway by herbicide 2,4,5-T and related phenoxycarboxylic acids. 6) Effects of DBCP, 2,4,5-T and Cd++ in regenerating rat liver. These studies may explain: (1) muscle weakness and paralysis at sublethal doses of 2,4,5-T and Cd++; (2) depressed placental function by Cd++, DBCP, and 2,4,5-T; and (3) the general toxic effects of Cd++, DBCP, and 2,4,5-T on regenerating tissues.
